CA2650478C

CA2650478C - Compositions comprising a dissociated glucocorticoid receptor agonist and an immunosuppressive agent for treating dry eye

Info

Publication number: CA2650478C
Application number: CA2650478A
Authority: CA
Inventors: Erning Xia; Zhenze Hu
Original assignee: Bausch and Lomb Inc
Current assignee: Bausch and Lomb Inc
Priority date: 2006-07-07
Filing date: 2007-06-20
Publication date: 2013-08-13
Anticipated expiration: 2027-06-20
Also published as: RU2009104002A; WO2008005686A2; TW200817377A; EP2051736A2; AU2007269421A1; RU2431502C2; TWI338689B; CN101484187A; US20080009437A1; CA2650478A1; BRPI0714155A2; KR20090033865A; AU2007269421B2; WO2008005686A3; JP2009542704A; MX2008015151A; WO2008005686A8; CN101484187B

Abstract

A composition for treating or reducing a dry eye condition or an ophthalmological disorder that has an etiology in inflammation comprises a dissociated glucocorticoid receptor agonist ("DIGRA"). The composition can be formulated for topical application, injection, or implantation.

Description

COMPOSITIONS COMPRISING A DISSOCIATED GLUCOCORTICOID
RECEPTOR AGONIST AND AN IMMUNOSUPPRESSIVE
AGENT FOR TREATING DRY EYE
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions for dry eye therapy.
In particular, the present invention relates to pharmaceutical compositions that comprise dissociated glucocorticoid receptor agonists ("DIGRAs") for the treatment of dry eye syndrome. In addition, the present invention relates to a method for treating or ameliorating the dry eye syndrome using such DIGRAs.
Dry eye, also known as keratoconjunctivitis sicca ("KCS"), is a common ophthalmological disorder affecting millions of people each year. Dry eye conditions can be caused by a variety of factors. There has been increasing evidence that inflammation may be an important factor in the pathogenesis of KCS. For example, inflammation of the lacrimal and meibomian glands can curb tear production. In addition, elevated levels of pro-inflammatory mediators, including IL-I, have been detected in the conjunctival tissues of patients afflicted with systemic autoimmune diseases, such as Sjogren's syndrome. These patients also suffer with severe dry eye.
Sjogren's syndrome is a chronic disorder in which white blood cells attack the moisture-producing glands, such as lacrimal and salivary glands. Dry eye may afflict individuals with differing severity. In mild cases, a patient may experience burning, a feeling of dryness, and other symptoms of ocular discomfort. In severe cases, vision may be substantially impaired. Although dry eye may have a variety of unrelated pathogenic causes, they all share as a common effect the breakdown of the ocular tear film, with dehydration of and subsequent damage to the exposed outer ocular surfaces.
Prior-art therapies for dry eye have included both palliative agents, such as artificial tear formulations, and drugs, such as topical steroids, topical retinoids (e.g., Vitamin A), oral pilocarpine, and topical cyclosporine. In general, the palliative therapies are capable of providing short-term relief from some of the symptoms of dry eye, but frequent application of the palliative products to the eye is required to maintain this relief, since these products generally do not eliminate the physiological sources of the dry eye conditions. The drug therapies that have been proposed in the prior art have had limited success in treating dry eye conditions. One reason for the limited efficacy of prior-art drug therapies has often been attributable to the inability of the drug to eliminate or reduce the root causes of the dry eye conditions. Steroidal drugs also can have side effects that threaten the overall health of the patient.
It is known that certain glucocorticoids (also referred to herein as , "corticosteroids") have a greater potential for elevating intraocular pressure ("TOP") than other compounds in this class. For example, it is known that prednisolone, which is a very potent ocular anti-inflammatory agent, has a greater tendency to elevate IOP than fluorometholone, which has moderate ocular anti-inflammatory activity. It is also known that the risk of IOP elevations associated with the topical ophthalmic use of glucocorticoids increases over time. In other words, the chronic (i.e., long-term) use of these agents increases the risk of significant IOP elevations. Unlike bacterial infections or acute ocular inflammation associated with physical trauma, which requires short-term therapy on the order of a few weeks, dry eye conditions require treatment for extended periods of time, generally several months or more. This chronic use of corticosteroids significantly increases the risk of IOP elevations. In addition, use of corticosteroids is also known to increase the risk of cataract formation in a dose- and duration-dependent manner. Once cataracts develop, they may progress despite discontinuation of corticosteroid therapy.
Chronic administration of glucocorticoids also can lead to drug-induced osteoporosis by suppressing intestinal calcium absorption and inhibiting bone formation.
Other adverse side effects of chronic administration of glucocorticoids include hypertension, hyperglycemia, hyperlipidemia (increased levels of triglycerides) and hypercholesterolemia (increased levels of cholesterol) because of the effects of these drugs on the body metabolic processes.
Therefore, there is a continued need to provide pharmaceutical compounds and compositions to treat or reduce the dry eye condition, which compounds and compositions cause a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or reduce the same condition.

SUMMARY OF THE INVENTION
In general, the present invention provides pharmaceutical compounds and compositions for treating or reducing in a subject a dry eye condition or other disorders that require rewetting of the eye (for example, disorders that require restoring normal tear function), which compounds and compositions cause a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or reduce the same condition or disorder.
In one aspect, the pharmaceutical compounds and compositions comprise at least a mimetic of a glucocorticoid in treating or reducing such a condition or disorder.
In another aspect, the pharmaceutical compounds and compositions comprise at least a dissociated glucocorticoid receptor agonist ("DIGRA").
In still another aspect, a pharmaceutical composition of the present invention comprises an ophthalmic topical formulation, injectable formulation, or implantable formulation or device.
In yet another aspect, said at least an adverse side effect is demonstrated in vitro or in vivo.
Other features and advantages of the present invention will become apparent from the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, a dissociated glucocorticoid receptor agonist ("DIGRA") is a compound that is capable of binding to the glucocorticoid receptor (which is a polypeptide) and, upon binding, is capable of producing differentiated levels of transrepression and transactivation of gene expression. A compound that binds to a polypeptide is sometimes herein referred to as a ligand.

As used herein, the term "alkyl" or "alkyl group" means a linear- or branched-chain saturated aliphatic hydrocarbon monovalent group, which may be unsubstituted or substituted. The group may be partially or completely substituted with halogen atoms (F, Cl, Br, or 1). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. It may be abbreviated as "Alk". , As used herein, the term "alkenyl" or "alkenyl group" means a linear-or branched-chain aliphatic hydrocarbon monovalent radical containing at least one carbon-carbon double bond. This term is exemplified by groups such as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.
As used herein, the term "alkynyl" or "alkynyl group" means a linear-or branched-chain aliphatic hydrocarbon monovalent radical containing at least one carbon-carbon triple bond. This term is exemplified by groups such as ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
As used herein, the term "alkylene" or "alkylene group" means a linear-or branched-chain saturated aliphatic hydrocarbon divalent radical having the specified number of carbon atoms. This term is exemplified by groups such as methylene, ethylene, propylene, n-butylene, and the like, and may alternatively and equivalently be denoted herein as -(alkyl)-.
The term "alkenylene" or "alkenylene group" means a linear- or branched-chain aliphatic hydrocarbon divalent radical having the specified number of carbon atoms and at least one carbon-carbon double bond. This term is exemplified by groups such as ethenylene, propenylene, n-butenylene, and the like, and may alternatively and equivalently be denoted herein as -(alkylenyI)-.
The term "alkynylene" or "alkynylene group" means a linear- or branched-chain aliphatic hydrocarbon divalent radical containing at least one carbon-carbon triple bond.

This term is exemplified by groups such as ethynylene, propynylene, n-butynylene, 2-butynylene, 3-methylbutynylene, n-pentynylene, heptynylene, octynylene, decynylene, and the like, and may alternatively and equivalently be denoted herein as -(alkyny1)-.
As used herein, the term "aryl" or "aryl group" means an aromatic carbocyclic monovalept or divalent radical of from 5 to 14 carbon atoms having a single ring (e.g., phenyl or phenylene), multiple condensed rings (e.g., naphthyl or anthranyl), or multiple bridged rings (e.g., biphenyl). Unless otherwise specified, the aryl ring may be attached at any suitable carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure.
Non-limiting examples of aryl groups include phenyl, naphthyl, antluyl, phenanthryl, indanyl, indenyl, biphenyl, and the like. It may be abbreviated as "Ar".
The term "heteroaryl" or "heteroaryl group" means a stable aromatic 5- to 14-membered, monocyclic or polycyclic monovalent or divalent radical, which may comprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic radical, having from one to four heteroatoms in the ring(s) independently selected from nitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or be quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. Non-limiting examples of heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, diazaindolyl, dihydroindolyl, dihydroazaindoyl, isoindolyl, azaisoindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridinyl, dihydrofuranopyrimidinyl, benzothienyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, dihydrobenzothienyl, dihydrothienopyridinyl, dihydrothienopyrimidinyl, indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl, imidazopyridinyl, benzthiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, benzoxazolyl, benzoxazinyl, benzoxazinonyl, oxazolopyridinyl, oxazolopyrimidinyl, benzisoxazolyl, purinyl, chromanyl, azachromanyl, quinolizinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, azacinnolinyl, phthalazinyl, azaphthalazinyl, quinazolinyl, azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, naphthyridinyl, dihydronaphthyridinyl, tetrahydronaphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.
The term "heterocycle", "heterocycle group", "heterocyclyl", "heterocyclyl group", "heterocyclic", or "heterocyclic group" means a stable non-aromatic 5-to 14-membered monocyclic or polycyclic, monovalent or divalent, ring which may comprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, having from one to three heteroatoms in at least one ring independently selected from nitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or be quaternized. As used herein, a heterocyclyl group excludes heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl groups. Unless otherwise specified, the heterocyclyl ring may be attached at any suitable heteroatom or carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. Non-limiting examples of heterocycles include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl;
tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, and the like.
The term "cycloalkyl" or "cycloalkyl group" means a stable aliphatic saturated to 15-membered monocyclic or polycyclic monovalent radical consisting solely of carbon and hydrogen atoms which may comprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring.
Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl, tetrahydronaphthyl (tetralin), I-decalinyl, bicyclo[2.2.21octanyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like.
The term "cycloalkenyl" or "cycloalkenyl group" means a stable aliphatic 5- to 15-membered monocyclic or polycyclic monovalent radical having at least onc carbon-carbon double bond and consisting solely of carbon and hydrogen atoms which may comprise one or more fused or bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, norbornenyl, 2-methylcyclopentenyl, 2-methylcyclooctenyl, and the like.
The term "cycloalkynyl" or "cycloalkynyl group" means a stable aliphatic 8- to 15-membered monocyclic or polycyclic monovalent radical having at least one carbon-carbon triple bond and consisting solely of carbon and hydrogen atoms which may comprise one or more fused or bridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to 15-membered bicyclic ring. Unless otherwise specified, the cycloalkynyl ring may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Exemplary cycloalkynyl groups include cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, and the like.
The term "carbocycle" or "carbocyclic group" means a stable aliphatic 3- to 15-membered monocyclic or polycyclic monovalent or divalent radical consisting solely of carbon and hydrogen atoms which may comprise one or more fused or bridged rings, preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring.
Unless otherwise specified, the carbocycle may be attached at any carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term comprises cycloalkyl (including spiro cycloalkyl), cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyl, and cycloalkynylene, and the like.
The terms "heterocycloalkyl", "heterocycloalkenyl", and "heterocycloalkynyl"
means cycloalkyl, cycloalkenyl, and cycloalkynyl group having at least a heteroatom in at least one ring, respectively, Glucocorticoids ("GCs") are among the most potent drugs used for the treatment of allergic and chronic inflammatory diseases. However, as mentioned above, long-term treatment with GCs is often associated with numerous adverse side effects, such as diabetes, osteoporosis, hypertension, glaucoma, or cataract. These side effects, like other physiological manifestations, are results of aberrant expression of genes responsible for such diseases. Research in the last decade has provided important insights into the molecular basis of GC-mediated actions on the expression of GC-responsive genes. GCs exert most of their genomic effects by binding to the cytoplasmic GC receptor ("GR").
The binding of GC to GR induces the translocation of the GC-GR complex to the cell nucleus where it modulates gene transcription either by a positive (transactivation) or negative (transrepression) mode of regulation. There has been growing evidence that both beneficial and undesirable effects of GC treatment are the results of undifferentiated levels of expression of these two mechanisms; in other words, they proceed at similar levels of effectiveness. Although it has not yet been possible to ascertain the most critical aspects of action of GCs in chronic inflammatory diseases, there has been evidence that it is likely that the inhibitory effects of GCs on cytokine synthesis are of particular importance. GCs inhibit the transcription, through the transrepression mechanism, of several cytokines that are relevant in inflammatory diseases, including IL-1f3 (interleukin-113), IL-2, IL-3, IL-6, IL-11, TNF-a (tumor necrosis factor-a), GM-CSF
(granulocyte-macrophage colony-stimulating factor), and chemokines that attract inflammatory cells to the site of inflammation, including IL-8, RANTES, MCP-1 (monocyte chemotactic protein-1), MCP-3, MCP-4, MIP-la (macrophage-inflammatory protein-1 a), and eotaxin. P.J. Barnes, Clin. Sci., Vol. 94, 557-572 (1998).
On the other hand, there is persuasive evidence that the synthesis of Ix13 kinases, which are proteins having inhibitory effects on the NF-KB proinflammatory transcription factors, is increased by GCs. These proinflammatory transcription factors regulate the expression of genes that code for many inflammatory proteins, such as cytokines, inflammatory enzymes, adhesion molecules, and inflammatory receptors. S. Wissink et al., Mol.
Endocrinol., Vol. 12, No. 3, 354-363 (1998); P.J. Barnes and M. Karin, New Engl. J.
Med., Vol. 336, 1066-1077 91997). Thus, both the transrepression and transactivation functions of GCs directed to different genes produce the beneficial effect of inflammatory inhibition. On the other hand, steroid-induced diabetes and glaucoma appear to be produced by the transactivation action of GCs on genes responsible for these diseases. H. Schacke et al., Pharmacol. Ther., Vol. 96, 23-43 (2002).
Thus, while the transactivation of certain genes by GCs produces beneficial effects, the transactivation of other genes by the same GCs can produce undesired side effects.
Therefore, it is very desirable to provide pharmaceutical compounds and compositions that produce differentiated levels of transactivation and transrepression activity on GC-responsive genes to treat or reduce chronic inflammatory conditions.
In general, the present invention provides pharmaceutical compounds and compositions for treating or reducing in a subject a dry eye condition or other disorders that require rewetting of the eye (for example, disorders that require restoring normal tear function), which compounds and compositions cause a lower level of at least an adverse side effect than at least a prior-art glucocorticoid used to treat or reduce the same condition or disorder. Such a condition or disorder has an etiology in chronic inflammation.
In one aspect, said at least an adverse side effect is selected from the group consisting of glaucoma, cataract, hypertension, hyperglycemia, hyperlipidemia (increased levels of triglycerides), and hypercholesterolemia (increased levels of cholesterol). In one embodiment, a level of said at least an adverse side effect is determined at about one day after said compounds or compositions are first administered to, and are present in, said subject. In another embodiment, a level of said at least an adverse side effect is determined about 30 days after said compounds or compositions are first administered to, and are present in, said subject. Alternatively, a level of said at least an adverse side effect is determined about 2, 3, 4, 5, or 6 months after said compounds or compositions are first administered to, and are present in, said subject.

In another aspect, said at least a prior-art glucocorticoid used to treat or reduce the same condition or disorder is administered to said subject at a dose and a frequency sufficient to produce the same beneficial effect on said condition or disorder as a compound or composition of the present invention after about the same elapsed time.
In still another aspect, said at least a prior-art glucocorticoid is selected from the , group consisting of 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, their physiologically acceptable salts, combinations thereof, and mixtures thereof. In one embodiment, said at least a prior-art glucocorticoid is selected from the group consisting of dexamethasone, prednisone, prednisolone, methylprednisolone, medrysone, triamcinolone, loteprednol etabonate, physiologically acceptable salts thereof, combinations thereof, and mixtures thereof. In another embodiment, said at least a prior-art glucocorticoid is acceptable for ophthalmic uses.
In one aspect, the pharmaceutical compounds and compositions comprise at least a mimetic of a glucocorticoid in treating or reducing such a condition or disorder.
In another aspect, the pharmaceutical compounds and compositions comprise at least a dissociated glucocorticoid receptor agonist ("DIGRA").

In still another aspect, the pharmaceutical compounds and compositions comprise a prodrug or a pharmaceutically acceptable salt of at least a DIGRA.
In still another aspect, said at least a DIGRA has Formula I.

BQ (I) A
wherein A and Q are independently selected from the group consisting of unsubstituted and substituted aryl and heteroaryl groups, unsubstituted and substituted cycloalkyl and heterocycloalkyl groups, unsubstituted and substituted cycloalkenyl and heterocycloalkenyl groups, unsubstituted and substituted cycloalkynyl and heterocycloalkynyl groups, and unsubstituted and substituted heterocyclic groups; RI and R2 are independently selected from the group consisting of hydrogen, unsubstituted C1-C15 (alternatively, C1-C10, or C1-05, or C1-C3) linear or branched alkyl groups, substituted C1-C15 (alternatively, C1-C10, or C1-05, or C1-C3) linear or branched alkyl groups, unsubstituted C3-C15 cycloalkyl groups, and substituted C3-C15 (alternatively, C3-C6, or C3-05) cycloalkyl groups; R3 is selected from the group consisting of hydrogen, unsubstituted CI-C15 (alternatively, C1-C10, or CI-Cs, or C1-C3) linear or branched alkyl groups, substituted C1-C15 (alternatively, CI-CIO, or C1-05, or C1-C3) linear or branched alkyl groups, unsubstituted C3-C15 (alternatively, C3-C6, or C3-05) cycloalkyl and heterocycloalkyl groups, substituted C3-C15 (alternatively, C3-C6, or C3-05) cycloalkyl and heterocycloalkyl groups, aryl groups, heteroaryl groups, and heterocyclylic groups;
B comprises a carbonyl, amino, divalent hydrocarbon, or heterohydrocarbon group; E is hydroxy or amino group; and D is absent or comprises a carbonyl group, -NH-, or ¨NR'-wherein R' comprises an unsubstituted or substituted C1-C15 (alternatively, C1-C10, or C1-05, or C1-C3) linear or branched alkyl group; and wherein RI and R2 together may form an unsubstituted or substituted C3-C15 cycloalkyl group.

In one embodiment, B can comprise one or more unsaturated carbon-carbon bonds.
In another embodiment, B can comprises an alkylenecarbonyl, alkyleneoxycarbonyl, alkylenecarbonyloxy, alkyleneoxycarbonylamino, alkyleneamino, , alkenylenecarbonyl, alkenyleneoxycarbonyl, alkenylenecarbonyloxy, alkenyleneoxycarbonylamino, alkenyleneamino, alkynylenecarbonyl, alkynyleneoxycarbonyl, alkynylenecarbonyloxy, alkynyleneoxycarbonylamino, alkynyleneamino, arylcarbonyloxy, aryloxycarbonyl, or ureido group.
In still another embodiment, A and Q are independently selected from the group consisting of aryl and heteroaryl groups substituted with at least a halogen atom, cyano group, hydroxy group, or C1-C10 alkoxy group (preferably C1-05 alkoxy group, or more preferably C1-C3 alkoxy group); RI, R2, and R3 are independently selected from the group consisting of unsubstituted and substituted C1-05 alkyl groups (preferably, C1-C3 alkyl groups); B is a C1-05 alkylene group (alternatively, C1-C3 alkyl groups); D is the ¨
NH- or ¨NR'- group, wherein R' is a C1-05 alkyl group (preferably, C1-C3 alkyl group);
and E is the hydroxy group.
In yet another embodiment, A comprises a dihydrobenzofuranyl group substituted with a halogen atom; Q comprises a quinolinyl or isoquinolinyl group substituted with a C1-C10 alkyl group; RI and R2 are independently selected from the group consisting of unsubstituted and substituted C1-05 alkyl groups (preferably, C1-C3 alkyl groups); B is a C1-C3 alkylene group; D is the ¨NH- group; E is the hydroxy group;
and R3 comprises a completely halogenated CI-Cm alkyl group (preferably, completely halogenated C1-05 alkyl group; more preferably, completely halogenated Ci-C3 alkyl group).
In still another embodiment, A comprises a dihydrobenzofuranyl group substituted with a fluorine atom; Q comprises a quinolinyl or isoquinolinyl group substituted with a methyl group; R' and R2 are independently selected from the group consisting of unsubstituted and substituted C1-05 alkyl groups; B is a C1-C3 alkylene group; D is the ¨NH- group; E is the hydroxy group; and R3 comprises a trifluoromethyl group.
In a further embodiment, said at least a DIGRA has Formula II or III.

(II) HO
(III) wherein R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C1-C10 (alternatively, C1-05, or C1-C3) alkoxy groups, unsubstituted C1-C10 (alternatively, C1-05, or C1 -C3) linear or branched alkyl groups, substituted C1-C10 (alternatively, C1-05, or C1-C3) linear or branched alkyl groups, unsubstituted C3-Cl0 (alternatively, C3-C6, or C3-05) cyclic alkyl groups, and substituted C3-C10 (alternatively, C3-C6, or C3-05) cyclic alkyl groups.

In still another embodiment, said at least a DIGRA has Formula IV.
H3c CH3 cF3 (IV) Methods for preparing compounds of Formula I, II, III, or IV are disclosed, for example, in U.S. Patents 6,897,224; 6,903,215; 6,960,581. Still other methods for preparing such compounds also can be found in PCT Patent Application WO 2006/050998 Al.
Non-limiting examples of compounds having Formula I include 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-methylquinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-trifluoromethyl-pentylamino]-1-methylisoquinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylaminolisoquino1-1(2H)-one, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifl uoromethyl-pentyl ami no]-2,6-d i methyl quinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-6-chloro-2-methylquinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentylamino]isoquinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]quinoline, 5-[4-(2,3-dihydro-5-fluoro-7-benzofurany1)-2-hydroxy -4-methy1-2-trifluoromethyl-pentylamino]quinolin-2[1HI-one, 6-fluro-5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2-methylquinoline, 8-fluoro-,544-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentylamino]-2-methylquinoline, 544-(5-fluoro-2,3-dihydrobenzofuran-7-y0-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino1-2-methylisoquinol-14214-one, and enantiomers thereof.

In yet another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of CI-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 ajkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, alkoxycarbonyl, aroyl, aminocarbonyl, alkyl aminocarbonyl, dialkyl aminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C5 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl;
(c) R3 is the trifluoromethyl group;
(d) B is C1-05 alkyl, C2-05 alkenyl, or C2-05 alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(f) E is the hydroxy group; and (g) Q is an azaindolyl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C5 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C5 alkanoylamino, Ci-05 alkoxycarbonylamino, CI-Cs alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, oxo, cyano, amino, and trifluoromethyl.
Non-limiting examples of these compounds include 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[2,3-c] pyridin-2-ylmethyl)pentan-2-ol;
1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-0 pyridin-2-ylmethyl)pentan-2-ol; 1, 1 , 1 -trifluoro-4-methyl-4-phenyl-2-( 1 H-pyrrolo[2,3 -c]pyridin-2-yl methyppentan-2-ol; 1,1,1-trifluoro-4-(4-fluoro-2-methoxypheny1)-4-methyl-2-(1H-pyrrolo[2,3-c] pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-methy1-4-pheny1-2-(1H-pyrrolo[3,2-c[pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(4-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-cl pyridin-2-ylmethyl)pentan-2-ol; 5-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-c[pyridin-2-ylmethypbutyl]phenol; 4-fluoro-214,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-c[pyridin-2-ylmethypbutyllphenol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-0 pyridin-2-ylmethyl)pentan-2-ol;
1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methyl-2-(3-methyl- 1 H-pyrrolo[2,3-c[pyridin-2-ylmethyl)pentan-2-ol; and 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy- 1 , 1 -dimethy1-3-( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]phenol.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, Ci-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either , nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl, or R1 and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;
(c) B is the methylene or carbonyl group;
(d) R3 is a carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-Ci-C8 alkyl, aryl-CI-C8 alkyl, aryl-Ci-C8 haloalkyl, heterocyclyl-C1-C8 alkyl, heteroaryl-CI-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups;
(e) D is the ¨NH- group;
(f) E is the hydroxy group; and (g) Q comprises a methylated benzoxazinone.
Non-limiting examples of these compounds include 2-benzy1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid(4-methyl- 1 -oxo- I H-benzo[d][1,2]oxazin-6-yDamide; 2-benzy1-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-methylpentanoic acid(4-methyl-1-oxo-IH-benzo[d][1,2]oxazin-6-yDamide; 2-cyclohexylmethy1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid(4-methyl- I -oxo- I H-benzo[d][ 1,21oxazin-6-yl)amide; 2-cyclohexylmethy1-4-(5-fluoro-2-hydroxyphenyI)-2-hydroxy-4-methylpentanoic acid(4-methyl- 1 -oxo- 1 H-benzo[d][1,2[oxazin-6-yl)amide; 2-benzy1-2-hydroxy-4-methyl-4-methylpentanoic acid(4-methyl-1-oxo-IH-benzo[d][1,21oxazin-6-yDamide; and 2-cyclohexylmethy1-2-hydroxy-4-methylpentanoic acid(4-methyl- 1 -oxo- 1 H-benzo[d][ 1 ,21 oxazin-6-yl)amide.
In still another embodiment, s4id at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, Ci-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, Ci-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, Ci-05 alkylaminosulfonyl, Ci-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by Ci-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl, or RI and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;
(c) R3 is the trifluoromethyl group;
(d) B is C1-05 alkyl, C2-05 alkenyl, or C2-05 alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;

(f) E is the hydroxy group; and (g) Q is an aryl or heteroaryl group one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, CI-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, CI-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of CI-C3 alkyl, C1-C3 alkoxy, acyl, C1-C3 silanyloxy, Ci-05 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, and trifluoromethyl.
Non-limiting examples of these compounds include 2-(3,5-difluorobenzyI)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 2-bipheny1-4-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 2-(3,5-dimethylbenzy1)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 2-(3-bromobenzy1)- 1 , 1,1 -trifluoro-4-(5-fluoro-2-methoxyphenyI)-4-methylpentan-2-ol; 2-(3,5-dichlorobenzy1)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol;
2-(3,5-bis-trifluoromethylbenzy1)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyI)-methylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-2-(3-fluoro-5-trifluoromethylbenzy1)-4-methylpentan-2-ol; 2-(3-chloro-2-fluoro-5-trifluoromethylbenzyl- )-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 444-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyllbenzonitrile; 2-(3,5-dibromobenzy1)-1,1, I -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-2-(2-fluoro-3-trifluoromethylbenzy1)-4-methylpentan-2-ol; 1, I, I -trifluoro-4-(5-fluoro-2-methoxypheny1)-2-(2-fluoro-5-trifluoromethylbenzy1)-4-methylpentan-2-ol.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl, heteroaryl, or C5-C15 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, Ci-05 alkanoylamino, C1-alkoxycarbonylamino, Ci-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen, C1-05 alkyl, C5-C15 arylalkyl, or R1 and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;
(c) R3 is the trifluoromethyl group;
(d) B is the carbonyl group or methylene group, which is optionally independently substituted with one or two substituent groups selected from C1-05 alkyl, hydroxy, and halogen;
(e) D is absent;

(f) E is the hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl; and (g) Q comprises a pyrrolidine, morpholine, thiomorpholine, piperazine, piperidine, 1H-pyridin-4-one, 1H-pyridin-2-one, 1H-pyridin-4-ylideneamine, 1H-quinolin-4-ylideneamine, pyran, tetrahydropyran, 1,4-diwpane, 2,5-diazabicyclo[2.2.11heptane, 2,3,4,5-tetrahydrobenzo[b][1,41diazepine, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydro-1H-quinolin-4-one, tetrahydroisoquinoline, decahydroisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indole, chroman, 1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroindazol-3-one, 3,4-dihydro-2H-benzo[1,41oxazine, 4H-benzo[1,41thiazine, 3,4-dihydro-2H-benzo[1,41thiazine, 1,2-dihydrobenzo[d] [1,3]oxazin4-one, 3,4-dihydrobenzo[1,41oxazin4-one, 3H-quinazolin4-one, 3,4-dihydro-1H-quinoxalin-2-one, 1H-quinnolin-4-one, 1H-quinazolin4-one, [1,51naphthyridin-4-one, 5,6,7,8-tetrahydro-1H-111,- 5]naphthyridin-4-one, 2,3-dihydro-1H-[1,5]naphthyridin-4-one, 1,2-dihydropyrido[3,2-d][1,3]oxazin-4-one, pyrrolo[3,4-c[pyridine-1,3-dione, 1,2-dihydropyrrolo[3,4-c[pyridin-3-one, or tetrahydro[b][1,4[diazepinone group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C5 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C5 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, acyl, aryl, benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, or ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl.
Non-limiting examples of these compounds include 2-(2,6-dimethylmorpholin-4-ylmethyl)- 1, 1 , 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1 -[4-(5-fluoro-2;methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl] -1H-quinolin-4-one; 144-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-3,5-dimethylpiperidin-4-one; 144-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-tri fl uoromethy lpenty11-3-methyl- 1 H-qu i no lin-4-one ; 1 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1}-2,3-dihydro-1H-quinolin-4-one; 11444-fluoropheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-1H-quinolin-4-one;

fluoropheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one;

fluoro-2-hydrox ypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1}-1H-quinolin-4-one; 1-114-pheny1-2-hydroxy-4-methyl- -2-trifluoromethylpenty1]-1H-quinolin-4-one; 1-[4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl[-1H-quinolin-4-one; 144-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-trifluoromethylpentyl[-1H-quinolin-4-one; 1-[4-(5-methy1-2,3-dihydrobenzofuran-7-y-1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; 1-[4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; 1-[4-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl[-IH-quinolin-4-one; 114-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-[ 1 ,5}naphthyridin-4-one; 1 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-2,4-dimethylpenty1}-3,5-dimethyl-1H-pyridin-4-one; 142-hydroxy-4-(2-methoxy-5-thiophen-2-ylpheny1)-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one;
1-[4-(6-bromobenzo[1,31dioxo1-4-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- I H-quinolin-4-one; 144-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-3-methyl-IH-quinolin-4-one; 142-hydroxy-4-(4-hydroxybipheny1-3-y1)-4-methyl-2-trifl uoromethylpentyI]- 1 H-quinolin-4-one ;
1 - { 4-[5-(3,5-dimethylisoxazo1-4-y1)-2-hydroxypheny11-2-hydroxy-4-methy1-2-trifluoromethylpentyl }-1H-quinolin-4-one; 142-hydroxy-4-(2-hydroxy-5-thiophen-ylpheny1)-4-methy1-2-trifluoromethylpenty1]- 1 H-quinolin-4-one; 1 - { 41543,5-dimethylisoxazol-4-y1)-2-methoxypheny1]-2-hydroxy-4-methy1-2-trifluoromethylpenty1}-1H-quinolin-4-one; 1-[2-hydroxy-4-methy1-4-(3-pyridin-3-ylpheny1)-2-trifluoromethylpenty1]-1H-quinolin-4-one; 4-methoxy-344,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(4-oxo-4H-quinolin-1-ylmethyl)butylThenzaldehyde; 142-hydroxy-4-(2-methoxy-5-thiophen-3-ylpheny1)-4-methy1-2-trifluoromethylpenty11-quinolin-4-one; 144-(5-furan-3-y1-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-quinolin-4-one; 112-hydroxy-4-(4-methoxybipheny1-3-y1)-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; I 44-(5-acety1-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyfl-1H-quinolin-4-one; 143,3,3-trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2-hydroxypropyl]-1H-quinolin-4-one; 1-(4-{3-[1-(benzyloxyimino)ethyllpheny11-2-hydroxy-4-methyl-2-trifluoromethylpenty1)-1H-quinolin-4-one; 144-(5-acety1-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty11- 1H-quinolin-4-one; 1-(2-hydroxy-4- {341-(methoxyimino)ethyllpheny1}-4-methyl-2-trifluoromethylpenty1)-1H-quinolin-4-one; 1-[4-(5-bromo-2-hydroxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty11-1H-quinolin-4-one; 1-(2-hydroxy-4- {311-(hydroxyimino)ethyllpheny11-4-methyl-2-trifluoromethylpenty1)-1H-quinolin-4-one; 144-(5-bromo-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll -1H-quinolin-4-one; 144-(3,5-difluoropheny1)-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; 14443,5-dimethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll -1 H-quinolin-4-one; 1- { 2-hydroxy-4-methy1-443-(2-methy141,31dioxolan-2-yppheny11-2-trifluoromethylpentyll-1H-quinolin-4-one; 144-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyfl-1 H- [1,5]naphthyridin-4-one; 144-(341,3[dioxan-2-ylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; 1- { 44343,5-dimethylisoxazol-4-yl)phenyl[-2-hydroxy-4-methyl-2-trifluoromethylpenty11-1H-quinolin-4-one; 144-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyI]-3,5-dimethyl-IH-pyridin-4-one; 144-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-2-hydroxymethy1-3,5-dimethyl- I H-pyridin-4-one; 144-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-trifluoromethylpentyll-3-hydroxymethyl-IH-quinolin-4-one; 144-(3-bromopheny1)-hydroxy-4-methy1-2-trifluoromethylpentyll- I H-quinolin-4-one; 144-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-6-methyl- I H-quinol in-4-one; 6-chloro-144-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- I H-quinolin-4-one; 1-[-4-(2-difluoromethoxy-5-fluorophenyI)-2-hydroxy-4-methyl-2-trifluoromethylpenty11- 1 H-quinolin-4-one; 1 -(4-bipheny1-3-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)- I H-quinol in-4-one; 1 42-hydroxy-4-(2-hydroxy-5-methylpheny1)-4-methy1-2-trifluoromethylpentyli- I H-quinolin-4-one;

hydroxy-4-(3 -isopropoxypheny1)-4-methyl-2-trifluoromethylpenty11- I H-quinol in-4-one;
I 44-(3-ethoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1 H-quinolin-4-one;
1 42-hydroxy-4-(2-methoxy-5 -methylpheny1)-4-methyl-2-trifluoromethylpentyll -quinolin-4-one; 114-(2,5-dimethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl] -1 H-quinolin-4-one ; I [2-hydroxy-4-(3 -methoxypheny1)-4-methy1-2-trifluoromethylpentyll -1 H-quinol in-4-one; 1- [4-(5-fluoro-2-hydrox ypheny1)-2-hydrox y-4-methy1-2-trifluoromethylpentyI]- 1,2-dihydroindazol-3-one; 7-fluoro-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll 1H-quinolin-4-one; 1 44-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-3,5-dimethyl-1 H-pyridin-4-one; 7-fluoro- I 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- IH-quinolin-4-one; 1-(2-hydroxy-4-methy1-4-pheny1-2-trifluoromethylhexyl)- 1 H-quinolin-4-one; 144-(4-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-H-quinolin-4-one; 144-(3,4-dimethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty 11 -1 H-quinolin-4-one; 8-fluoro- I 44-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-quinolin-4-one; 6-fluoro- I 44-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl] -I H-quinolin-4-one; 7-chloro- 1 44-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- 1H-quinolin-4-one; I 44-(5-fluoro-2-isopropoxypheny1)-hydroxy-4-methy1-2-trifluoromethylpenty1J-H-quinolin-4-one; 144-(2-ethoxy-5 -fluoropheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl[- IH-quinolin-4-one;

fluoro-I 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl] -1 H-quinolin-4-one; 6-fluoro- 114-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- 1 H-quinolin-4-one; 1 42-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]- I H-quinolin-4-one;

hydroxy-4-methy1-4-(5-methylsulfany1-2,3-dihydrobenzofuran-7-y1)-2-trifl uoromethylpentyl] -1 H-quinol in-4-one; 7-chloro- 1 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl[- I H-quinol in-4-one; 3-chloro- 1 44-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl[-5-trifluoromethyl-I H-pyridin-2-one; 1 -[2-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-methy1-2-trifluoromethylpenty11-3-methy1-1H-quinolin-4-one; 142-hydroxy-4-(2-methoxy-5-pyridin-3-ylpheny1)-4-methyl-2-trifluoromethylpentyl]- 1 H-quinol in-4-one; 1 -[2-hydroxy-4-(2-hydroxy-3,5-dimethylpheny1)-4-methy1-2-trifluoromethylpentyll-H-quinolin-4-one; 144-(341,31dioxan-2-y1-4-fluoropheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one; 2-( 1,1 -dioxo-2,3-dihydro- 1H- 1 X6-benzo[ 1 ,41 thiazin-4-ylmethyl)- 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 2-(2,3-dihydrobenzo[1,4]oxazin4-ylmethyl)-1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 114-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-H-quinolin-4-one; 1-[4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-H-[1,5]naphthyridin-one; 144-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-H-quinolin-4-one; 1-[4-(2,4-dimethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl] -1H-quinolin-4-one; 1 44-(4-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-H-quinolin-4-one; 144-(3-fluoro-4-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-quinolin-4-one; 1-(4-benzo[1,3]dioxo1-4-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-1H-quinolin-4-one; 1-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1,2-dihydroindazol-one; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1-oxo-2,3-dihydro-111-1X4-benzo[1,4- ]thiazin-4-ylmethyl)pentan-2-ol; 144-(5-fluoro-2-methoxypheny1)-hydroxy-4-methy1-2-trifluoromethylpenty1]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin--4-one; 144-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-3-methyl-1H-quinolin-4-one; 1-[2-hydroxy-4-(2-methoxy-3,5-dimethylpheny1)-4-methy1-2-trifluoromethylpentyll-1H-quinolin-4-one; 142-hydroxy-4-(2-hydroxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpentyll-1H-quinolin-4-one;
and 112-hydroxy-4-(2-hydroxy-5-pyridin-5-ylpheny1)-4-methy1-2-trifluoromethylpenty11-1H-quinolin-4-one.
In still another embodiment, said at least a DIGRA has Formula I, wherein A, RI, R2, B, D, E, and Q have the meanings disclosed immediately above, and R3 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C1-C8 alkyl, carboxy, alkoxycarbonyl, aryl-Ci-C8 alkyl, aryl-C1-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-C1-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, CI-Cs alkanoyl, aroyl, C1-05 alkoxycarbonyl, C1-Cs alkanoyloxy, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-Cs dialkylaminocarbonyl, CI-Cs alkanoylamino, CI-Cs alkoxycarbonylamino, C1-Cs alkylsulfonylamino, CI-Cs alkylaminosulfonyl, CI-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by CI-Cs alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R3 cannot be trifluoromethyl.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl, heteroaryl, or C5-C15 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of CI-Cs alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, CI-Cs alkoxy, C2-alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-alkylaminocarbonyloxy, CI-Cs dialkylaminocarbonyloxy, C1-05 alkanoylamino, CI-Cs alkoxycarbonylamino, C1-Cs alkylsulfonylamino, aminosulfonyl, CI-Cs alkylaminosulfonyl, CI-Cs dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, CI-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) R1 and R2 are each independently hydrogen or CI-Cs alkyl, or R1 and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;

(c) R3 is the trifluoromethyl group;
(d) B is the carbonyl group;
(e) D is the ¨NH- group;
(f) E is the hydroxy group; and (g) Q comprises an optionally substituted phenyl group having the formula xl la X2 wherein X1, X2, X3 and X4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-05 alkyl, C2-alkenyl, C2-05 alkynyl, Ci-05 alkoxy, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, Ci-05 alkanoyl, C1-05 alkoxycarbonyl, C1-C5 acyloxy, Ci-05 alkanoylamino, Ci-05 carbamoyloxy, urea, aryl, and amino wherein the nitrogen atom may be independently mono- or di-substituted by C1-05 alkyl, and wherein said aryl group is optionally substituted by one or more hydroxy or C1-alkoxy groups, and wherein either nitrogen atom of the urea group may be independently substituted by C1-05 alkyl; or Q is an aromatic 5- to 7-membered monocyclic ring having from one to four heteroatoms in the ring independently selected from nitrogen, oxygen, and sulfur, optionally independently substituted with one to three substituent groups selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-05 alkoxy, C1-alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, C1-05 alkanoyl, C1-05 alkoxycarbonyl, C1-05 acyloxy, C1-05 alkanoylamino, C1-05 carbamoyloxy, urea, aryl optionally substituted by one or more hydroxy or C1-05 alkoxy groups, and amino wherein the nitrogen atom may be independently mono- or di-substituted by C1-05 alkyl, and wherein either nitrogen atom of the urea group may be independently substituted by C1-05 alkyl.
Non-limiting examples of these compounds include 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanoic acid (3,5-dichloro-pheny1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydro?,cy-4-methy1-2-trifluoromethyl-pentanoic acid (3-chloro-phenyl)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-trifluoromethyl-pentanoic acid (2-chloro-phenyl)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (2,6-dichloro-pyrimidin-4-yI)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (2,6-dichloro-pyridin-4-y1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (2,3-dichloro-phenyl)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (3,5-dimethyl-pheny1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (3,5-bis-trifluoromethyl-pheny1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (2,5-dichloro-phenyl)-amide;
4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (3-bromo-pheny1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (3,5-difluoro-pheny1)-amide; 4-(5-fluoro-2-hydroxy-pheny1)-2-hydroxy-4-methy1-2-trifluoromethyl-pentanoic acid (3,5-dibromo-pheny1)-amide.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, Ci-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, Ci-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl;
(c) R3 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-Ci-C8 alkyl, aryl-Ci-C8 alkyl, aryl-Ci-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-Ci-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-Cs alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, C1-05 alkanoyl, aroyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-05 dialkylaminocarbonyl, C1-05 alkanoylamino, Ci-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or Ci-alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R3 cannot be trifluoromethyl;
(d) B is C1-05 alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(f) E is the hydroxy group; and (g) Q comprises an azaindolyl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or C1-alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl.
Non-limiting examples of these compounds include 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[2,3-clpyridin-2-ylmethyppentan-2-ol;
1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[2,3-b[pyridin-2-ylmethyppentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyppentan-2-ol; 4-fl uoro-244,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-c[pyridin-2-ylmethyl)butyllphenol; 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-Npyridin-2-ylmethyl)butyl]phenol; 4-fluoro-2-114,4,4-trifluoro-3-hydroxy-1 , 1 -dimethy1-3-( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyll phenol; 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[3,2-blpyridin-2-ylmethyl)butyllphenol;
1, 1, I -trifluoro-4-(3-fluoropheny1)-4-methyl-2-( 1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(4-fluoropheny1)-4-methy1-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 4-(2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-4-methy1-2-( 1 H-pyrrolo[2,3-c]pyridin-2-yelmethyppentan-2-ol; 4-(2,3-dihydrobenzofuran-7-y1)- 1, I , I -trifluoro-4-methyl-2-( I H-pyrrolo[3,2-c[pyridin-2-yelmethyl)pentan-2-ol;

1,1,1 -trifluoro-4-methyl-4-phenyl-2-( 1 H-pyrro1o[2,3-c]pyridine-2-ylmethy1)pentan-2-ol ;
1,1,1 -trifluoro-4-(4-fluoro-2-methoxypheny1)-4-methyl-24 1 H-pyrrolo[2,3-c]
pyridin-2-ylmethyl)pentan-2-ol ; 1,1,1 -trifluoro-4-(4-fluoro-2-methoxypheny1)-4-methyl-pyrrolo[3,2-cl pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-methy1-4-pheny1-2-(1H-pyrrolo[3,2-c[pyridin-2-ylmethyppentan-2-ol; 1,1,1-trifluoro-4-(4-fluoropheny1)-4-methy1-2-( 1 H-pyrrolo[3,2-c[pyridin-2-ylmethyl)pentan-2-ol; 5-fluoro-2-[4,4,4-trifluoro-3-hydroxy- 1,1 -dimethy1-3-( 1 H-pyrrolo[2,3-clpyridin-2-ylmethyl)butyliphenol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methyl-2-( 1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methyl-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyppentan-2-ol; 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy- 1,1 -dimethy1-3 -(3-methyl-1 H-pyrrolo[2,3-c[pyridin-2-ylmethyl)butyliphenol ;

5-fluoro-2-[4,4,4-trifluoro-3-hydroxy- 1 , 1 -dimethy1-3-( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyl]pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-(1H-pyrrolo[2,3-c[pyridine-2-ylmethyl)pentan-2-ol; 4-fluoro-214,4,4-trifluoro-3 -hydroxy- 1 , 1 -dimethy1-3-( 1 H-pyrrolo[2,3 -413 -methylpyridint-2-ylmethyl)butyliphenol; 4-fluoro-244,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-042-fluoropyridin1-2-ylmethypbutyliphenol; and 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(1H-pyrrolo[2,3-042-trifluoromethylpyridin]-ylmethyl)butyllphenol.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-Cs alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, Ci-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, CI-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, Ci-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) R1 and R2 are each independently hydrogen or C1-05 alkyl, or R1 and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring; , (C) R3 is the trifluoromethyl group;
(d) B is C1-05 alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(f) E is the hydroxy group; and (g) Q comprises a heteroaryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, CI-05 alkylaminosulfonyl, CI-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, acyl, C1-C3 silanyloxy, C1-05 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or trifluoromethyl.
Non-limiting examples of these compounds include 4-cyclohexy1-1,1,1-trifluoro-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 4-pyrimidin-5-y1-244,4,4-trifluoro-hydroxyl , 1 -dimethy1-3 -( 1 H-pyrrolo[2,3 -c] pyridin-2-ylmethyl)butyl[
phenol; 4-pyrimidin-5-y1-2-[4,4,4-trifluoro-3-hydroxy- 1,1 -dimethy1-3-( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)butyllphenol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(3-methyl-IH-pyrrolo[3,2-clpyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyppentan-2-ol;
1,1,1-trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(3-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 2-(4,6-dimethy1-1H-pyiTolo[3,2-clpyridin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol;
dimethy1-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-pyrrolo[3,2-b[pyridine-5-carbonitrile; 1,1 ,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(6-methyl-1H-pyrrolo[3,2-cipyridin-2-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(4-methyl- 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol; 244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-4-methyl- 1H-pyrrolo[3,2-clpyridine-6-carbonitrile; 214-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-1H-pyrrolo[2,3-clpyridine-5-carbonitrile; 244-(5-fluoro-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl[- 1 H-pyrrolo[3,2-c]pyridine-4-carbonitrile; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-thieno[2,3-d]pyridazin-2-ylmethylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(5H-pyrrolo[3,2-c[pyridazin-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methyl-2-(2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(1H-pyrrolo[2,3-d]pyridazin-2-ylmethyl)pentan-2-ol;

(4,6-dimethyl-H-pyrrolo[3,2-c[pyridin-2-ylmethyl)- 1, 1 , 1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-(4,6-dimethyl -1 H-pyrrolo[3 ,2-c] pyridin-2-ylmethyl)- 1,1,1 -trifluoro-4-methylpentan-2-ol; 2-[4-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyll -1 H-pyrrolo[3,2-b[pyridine-5-carbonitrile; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-1 >1,1 -trifluoro-4-methy1-2-(3-methyl- 1 H-pyrrolo[2,3-c[pyridin-2-ylmethyppentan-2-ol ; 1,1,1 -ffifluoro-4-(5-fluoro-2-methylpheny1)-4-methyl-2-(5H-pyffolo[3,2-c[- pyridazin-ylmethyl)pentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- I , 1, 1 -trifluoro-4-metby1-2-(5H-pyrrolo[3,2-c]pyridazin-6-ylmethyl)pentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1,1 -trifluoro-4-methyl-2-( 1 -H-pyrrolo[2,3-d]pyridazin-2-ylmethyppentan-2-ol; 1,1, 1-trifluoro-4-(5-fluoro-2-methoxypheny1)-2-(7-fluoro-pyrrolo[2,3 -cl pyridin-2ylmethyl)-4-methylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(4-methyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-ol; 2-(5,7-dichloro- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)- 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(5-trifluoromethyl- 1 H-pyrrolo[2,3-cipyridin-2-ylmethyppentan-2-ol;
1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-2-(5-methoxy- 1 H-pyrrolo[2,3-c]pyridin-ylmethyl)-4-methylpentan-2-ol; 1,1, 1-trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(4-methyl- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; I, 1 , 1 -trifluoro-4-(5-fluoro-2-methylpheny1)-2-(5-isopropoxy-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol; 1, 1, 1-trifluoro-4-(5-fluoro-2-methylpheny1)-2-(5-methoxy- 1 H-pyrrolo[2,3-c] pyridin-2-ylmethyl)-4-methylpentan-2-ol ; 4-(5-chloro-2,3 -dihydrobenzofuran-7-y1)-1 , 1 , 1 -trifluoro-2-(5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol;
1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-2-(7-fluoro- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1 -trifluoro-4-methy1-2-(5-trifluoromethyl- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol;
1 , 1, 1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(5-trifluoromethyl- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol ; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-1,1,1 -trifluoro-2-(5-isopropoxy- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- I , 1, 1 -trifluoro-2-(7-fluoro- 1 H-pyrrolo[2,3-cipyridin-2-ylmethyl)-4-methylpentan-2-ol ; 4-(5-chloro-2,3-dihydrobenzofuran-7-yI)-2-(5 -dimethylamino- 1 H-pyrrolo[2,3-Opyridin-2-ylmethyl)-1 , 1 , 1 -trifluoro-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7 -yI)- 1 , 1 , 1 -trifluoro-4-methyl-2-(5-piperidin- 1 -yl- 1 H-pyrrolo[2,3-clpyridin-2-ylmethyppentan-2-ol ; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1, 1, 1 -trifluoro-4-methyl-2-(5-morphol in-4-yl- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(5-piperidin- 1 -yl- I H-pyrrolo[2,3-c[pyridin-2-ylmethyppentan-2-o!; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-(5-ethoxy- 1 H-pyrrolo[2,3-c] pyridin-2-ylmethyl)- 1 , 1 , 1-trifluoro-4-methylpentan-2-ol; 2-(5-benzyloxy- 1H-pyrrolo[2,3-c[pyridin-2-ylmethy1)-1 , 1, 1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methylpentan-2-ol; 2-(5-benzyloxy- 1 H-pyrrolo[2,3-c[pyridin-2-ylmethyl)-4-(5 -chloro-2,3-dihydrobenzofiran-7-y!)- 1, 1, 1 -trifluoro-4-methylpentan-2-ol; 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxyphenyI)-2-(5-chloro-IH-pyrrolo[2,3-c- 1pyridin-2-ylmethyl)-4-methylpentan-2-ol; 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-[5-(methylamino)- 1H-pyrrolo[2,3-clpyridin-2-ylmethylipentan-2-ol; 1,1, 1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(5-amino- 1H-pyrrolo[2,3-Opyridin-2-ylmethyl)pentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(6-amino- 1H-pyrrol- o[2,3-clpyridin-2-ylmethyl)pentan-2-ol;
4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1,1 -trifluoro-2-(5-amino- 1H-pyrrolo[2,3-clpyridin-2-ylmethyl)-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-1, I , 1 -trifluoro-4-methyl-2-(5-methylamino- 1H-pyrrolo[2,3-clpyridin-2-ylmethyl)pentan-2-ol; 7- [4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyn-I H-pyrrolo[2,3-b]pyridin-7-ium chloride; 644-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1J-2-methyl- 1H-pyiTolo[2,3-c]pyridin-6-ium chloride; 4-(5-bromo-2,3-dihydrobenzofuran-7-y1)- 1, 1, 1 -trifluoro-4-methyl-2-( 1H-pyrrolo[2,3-clpyridin-2-ylmethyl)pentan-2-ol; 1, 1, 1 -trifluoro-4-methy1-4-(5-methy1-2,3-dihydrobenzofuran-7-y1)-2-( 1H-pyrrolo[2,3-cl pyridin-2-ylmethyl)pentan-2-ol;
4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1, 1-trifluoro-4-methy1-2-(1H-pyrrolo[2,3-c[pyridin-2-ylmethyl)pentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-pyrrolo[2,3-b1 pyridin- 1 -ylmethylpentan-2-ol; I , 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(6-oxy- 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyppentan-2-ol;
I , 1, 1 -trifluoro-4-(5-fltioro-2-methoxypheny1)-4-methyl-2-pyrrolo[2,3-clpyridin- 1 -ylmethylpentan-2-ol; 2-benzo[b]thiophen-2-ylmethyl- 1 , 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1, 1 , I -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-thieno[2,3-c]pyridin-2-ylmethylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-2-indazol- 1 -ylmethy1-4-methylpentan-2-ol; 1,1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-pyrazolof 1 ,5-a[pyridin-2-ylmethylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,4-dimethyl- I -thieno[2,3-c[pyridin-2-ylpentan-2-ol; 4-(5-fluoro-2-methylpheny1)-2,4-dimethyl- I -thieno[2,3-c]pyridin-2-ylpentan-2-ol;
1, I , I -trifluoro-4-(5-fluoro-2-methoxypheny1)-2-furo[2,3-clpyridin-2-ylmethy- 1-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-yI)- 1 -furo[2,3-c[pyridin-2-y1-2,4-dimethylpentan-2-ol; 4-(5-fluoro-2-methylpheny1)- 1 -furo-[2,3-c[pyridin-2-y1-2,4-, dimethylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methyl-2-( 1 H-pyrrolo[3,2-c[pyridin-2-ylmethyppentan-2-ol- ; I , 1 , 1 -trifluoro-4-methy1-4-(5-methy1-2,3-dihydrobenzofuran-7-y1)-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1,1 -trifluoro-4-methy1-2-(1H-pyrrolo[3,2-clpyridin-2-ylmethyppentan-2-ol; 4-(5-bromo-2,3-dihydrobenzofuran-7-yI)- 1,1 , trifluoro-4-methyl-2-( 1H-pyrrolo[3,2-0 pyridin-2-ylmethyl)pentan-2-ol ; 2-(3 -dimethylaminomethyl- 1H-pyrrolo[3,2-clpyridin-2-ylmethyl)- 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxyphenyI)-4-methy1-2-pyrrolo[3,2-clpyridin- 1 -ylmethylpentan-2-ol; 1, 1 >1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-pyrrolo[3,2-b]pyridin-1 -ylmethylpentan-2-ol; 1,1 , trifluoro-4-(5-fluoro-2-methoxypheny1)-2-furo[3,2-c]pyridin-2-ylmethyl-4-methylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-1 ,1 , 1 -trifluoro-4-methy1-2-pyrrolo[3,2-blpyridin-1-ylmethylpentan-2-ol; 1, 1, 1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-thieno[3 ,2-c]pyridin-2-ylmethylpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1,1 -trifluoro-4-methy1-2-thieno[3,2-clpyridin-ylmethylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-pyrrolo[3,2-blpyridin- 1 -ylmethylpentan-2-ol; 1, 1, 1 -trifluoro-4-(5-fluoro-methylpheny1)-4-methy1-2-thieno[3 ,2-c]pyridin-2-ylmethylpentan-2-ol; 4-fluoro-(4,4,4-trifluoro-3 -hydroxy- 1,1 -dimethy1-3-thieno[3,2-c[pyridin-2-ylmethylbutyl)phenol;
4-fluoro-2-(4,4,4-trifluoro-3-furo[3,2-clpyridin-2-ylmethyl-3-hydroxy- 1 , I -dimethylbutyl)phenol; 4-fluoro-2-(4,4,4-trifluoro-3-hydroxy- 1 , 1-dimethy1-3-pyrrolo[3,2-b]pyridin- 1 -ylmethylbutyl)phenol; 244-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11- 1 H-indole-6-carboxylic acid; 244-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyn- I H-indole-6-carboxylic acid dimethylamide; { 214-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indo1-6-y1 I morpholin-4-ylmethanone; 244-(5-fluoro-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-indole-6-carboxylic acid dimethylamide; {24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indol-6-y1} morpholin-4-ylmethanone; 24445-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-indole-6-carboxylic acid amide; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indole-6-carboxylic acid amide; 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1 , 1 -dimethy1-3-(5-nitro-1H-indo1-2-ylmethyl)butyliphenol; 2-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indole-6-carbonitrile;
2-[445-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indole-6-carbonitrile; N- 24445 -fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indo1-5-yllacetamide; 1,1,1 -trifluoro-4-(4-fluoro-2-methoxypheny1)-2-(7-fluoro-4-methyl- 1H-indo- 1-2-ylmethyl)-4-methylpentan-2-ol; 5-fluoro-2-[4,4,4-trifluoro-3-(7-fluoro-4-methyl- 1H-indo1-2-ylmethyl)-3-hydroxy-1 ,1 -dimethylbutyllphenol; 2444341,3 ]dioxolan-2-ylpheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]-1H-indole-5-carbonitrile; 24445-fluoro-2-methoxypheny1)-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indole-5-carboxylic acid-2-trimethylsilanylethyl ester; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-trifluoromethylpentyl]-1H-indole-5-carboxylic acid; 24444-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty- 1]-4-methyl-1H-indole-6-carbonitrile;
{ 244-(5-Fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indo1-5-yllpiperidin- 1-ylmethanone; 2-[445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-trifluoromethylpenty1]-1H-indole-5-carboxylic acid methylamide; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indol-5-yllpyrrolidin-1 -ylmethanone; 1 - f 24445 -fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]lH-indole-5-carbonyllpiperidin-4-one; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-1H-indole-5-carboxylic acid (2-hydroxyethyl)amide; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1 H- indo1-5-y1 1 (4-hydroxypiperidin- 1 -yl)methanone; { 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]- 1H-indo1-yl 1(3 -hydroxypyrrolidin- 1 -yl)methanone; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-IH-indole-5-carboxylic acid cyanomethylamide; 244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indole-5-carboxylic acid (2-dimethylaminoethyl)amide; 24445-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-tri fl uoromethylpenty I] - 1 H-indo1-5-y1 } (4-methylpiperazin- 1 -yl)methanone; ({214-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-indole-5-carbonyl } amino)acetic acid methyl ester;
244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- 1 H-indole-5-carboxylic acid carbamoylmethylamide; 4-({2-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty11-1H-indole-S-carbonyl } amino)butyric acid methyl ester; ({244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- 1 H-indole-5-carbonyl } amino)acetic acid; 4-( 244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl} -I H-indole-5-carbonyl }amino)butyric acid; 244-(3-dimethylaminomethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-1H-indole-5-carbonitrile; 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(5-trifluoromethy1-1H-indo1-2-ylmethyl)butyllphenol; 2-[4-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-methyl- 1H-indole-6-carbonitrile; 242-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methyl-2-trifluoromethylpenty11-4-methy1-1H-indole-6-carbonitrile; 244-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-indole-5-carboxylic acid; 214-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1H-indole-carboxylic acid amide; 244-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-indole-5-carboxylic acid dimethylamide; 2-[4-(5-Bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-indole-5-carboxylic acid cyanomethylamide; {244-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-indo1-5-yllpyrrolidin-1-ylmethanone;
{244-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoro-methylpenty1]-1H-indo1-5-yllmorpholin-4-ylmethanone; 244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-1H-indole-5-carboxylic acid amide; {244-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1 H-indo1-5-y1 lmorpholin-4-ylmethanone; 2-(4-benzo[ 1 ,3]dioxo1-4-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-4-methyl-1H-indole-6-carbonitrile;
1, 1,1-trifluoro-4-methy1-4-pheny1-2-quinolin-4-ylmethylhexan-2-ol; 2-[2-hydroxy-4-methy1-4-(5-methylsulfany1-2- ,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]- 1 H-indole-3 -carbonitrile; 7-(4,4,4-trifluoro-3-hydroxy-1 ,1-dimethy1-3-quinolin-ylmethylbutyI)-2,3-dihydrobenzofuran-5-carbonitri le ; 242-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methyl-2-trifluoromethylpentyl[-indole-3 -carbonitrile; 242-hydroxy-4-(2-hydroxy-5-methylpheny1)-4-methyl-2-trifluoro-methylpenty11-4-methyl- 1 H-indole-6-carbonitrile; 1,1,1 -trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-(5-methylsulfanyl- I H-indo1-2-ylmethyl)pentan-2-0l; 242rhydroxy-4-(2-methoxy-5-methylsulfanylpheny1)-4-methyl-2-trifluoromethylpentylF 1H-indole-3-carbonitrile; 242-Hydroxy-4-(5-methanesulfony1-2-methoxypheny1)-4-methyl-2-trifluoromethylpenty11-1H-indole-3-carbonitrile; 244-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-indole-5-sulfonic acid dimethylamide; 1,1,1 -trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-y- 1)-4-methyl-2-(5-phenyl- 1H-indo1-2-ylmethyl)pentan-2-ol; 244-(5 -tert-buty1-2-hydroxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyli-1H-indole-3-carbonitrile; 242-hydroxy-4-(2-hydroxy-5-isopropylpheny1)-4-methy1-2-trifluoromethylpenty11- 1H-indole-3-carbonitrile; 242-hydroxy-4-(2-hydroxy-3,5-dimethylpheny1)-4-methy1-2-trifluoromethylpenty11-1H-indole-3-carbonitrile;

hydroxy-4-(5-hydroxy-2,4-dimethylpheny1)-4-methy1-2-trifluoromethylpentyl[- 1H-indole-3 -carbonitrile; 24445 -tert-buty1-2-methoxypheny1)-2-hydrox y-4-methy1-trifluoromethylpentylF 1H-indole-3-carbonitrile; 244-(5-tert-buty1-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentylF 1-methyl- 1H-indole-3-carbonitrile;

hydroxy-4-(5-isopropy1-2-methoxypheny1)-4-methyl-2-trifluoromethylpentyll - 1H-indole-3-carbonitrile; 242-hydroxy-4-(5-isopropy1-2-methoxypheny1)-4-methyl-2-trifluoromethylpenty1]- 1 -methyl- I H-indole-3-carbonitrile; 242-hydroxy-4-(2-hydroxy-5-methanesulfonylpheny1)-4-methy1-2-trifluoromethylpenty1J- 1H-indole-3-carbonitrile; 2-[2-hydroxy-4-(2-methoxy-5 -methylpheny1)-4-methyl-2-trifluoromethylpentyl] -4-methyl-1 H-indole-6-carbonitrile; 1, 1 , 1 -trifluoro-4-methy1-2-quinolin-4-ylmethy1-4-o-tolylpentan-2-ol; 1,1,1-trifluoro-4-methy1-2-quinolin-4-ylmethy1-4-m-tolylpentan-2-ol;
1,1,1 -trifluoro-4-(2-fluorophenyI)-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; I, 1 , 1 -trifluoro-4-(2-fluoropheny1)-4-methyl-2-quinol in-4-ylmethylpentan-2-o!; 1,1,1 -trifluoro-4-(3-fluoropheny1)-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; I , 1 , I -trifluoro-4-(3-fluoropheny1)-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 1 , 1 , 1 -trifluoro-4-(4-fluoropheny1)-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 1 , 1 ,1 -trifluoro-4-(4-fluoropheny1)-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 3 -(4,4,4-trifluoro-3-hydroxy-1,1 -dimethy1-3-quinolin-4-ylmethylbutyl)phenol; 1,1,1 -trifluoro-4-methy1-2-quinolin-4-ylmethy1-4-(2-trifluoromethylphenyl)pentan-2-ol; 1,1,1 -trifluoro-2-( 1 H-indo1-2-ylmethyl)-4-methyl -4-(4-trifluoromethylphenyl)pentan-2-ol; I , I , 1 -trifluoro-4-methy1-2-quinolin-4-ylmethy1-4-(4-trifluoromethylphenyl)pentan-2-ol; 4-(3-chloropheny1)-1,1,1 -trifluoro-2-( I H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 4-(3-chlorophenyI)- I
, I , I ,-trifluoro-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 4-(4-dimethylaminopheny1)-1,1,1 -trifluoro-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 4-biphenyl-3-yl- 1,1,1 -trifluoro-4-methy1-2-quinol in-4-ylmethylpentan-2-ol; 4-(3-bromophenyI)- 1, 1, 1-trifluoro-2-( I H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 4-(2-difluoromethoxy-5-fluoropheny1)-1 , 1 , 1 -trifluoro-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 4-biphenyl-3 -yl- 1, 1, 1 -trifluoro-2-( 1H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 4-(4-dimethylaminopheny1)- 1,1 , trifluoro-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 244-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- 1,6-dihydropyrrolo[2,3-c]pyridin-5-one; 2-[4-(5-Fluoro-2-methylpheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-6-methyl-1 ,6-dihydropyrrolo[2,3-c[pyridin-5-one; 2-[4-(5-fluoro-2-methyl- pheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll -4-methyl-1 ,4-dihydropyrrolo[3,2-Npyridin-5-one;
1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-2-(6-methoxy- 1H-pyrrolo[3,2-clpyridin-2-ylmethyl)-4-methylpentan-2-ol; 2- [4-(5-fluoro-2-methy lpheny1)-2-hydrox y-4-methy1-2-trifluoromethylpenty1]-5-methyl- 1,5-dihydropyrrolo[3,2-c]pyridin-6-one; 2-[4-(5-fluoro-2-methyl- phenyl)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]- 1,3a-dihydropyrrolo[3,-2-c]pyridin-6-one; 244-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyfl- 1,7-dihydropyrrolo[3,2-c[pyridine-4,6-dione; 6-[4-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trfluoromethylpenty1]-3 -methyl- I ,7-dihydropyrrolo[2,3-d[pyrimidine-2,4-dione; 244-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoro- methylpentyll- 1 ,6-dihydropyrrolo[2,3-c]pyridin-5-one;
2-[4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-6-methyl- 1 ,6-dihydropyrrolo[2,3-Opyridin-5-one; 244-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll -1 ,4-dihydropyrrolo[3,2-b[pyridin-5-one; 244-(5 -chloro-2,3 -dihydrobenzofiran-7-yI)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-4-methyl- 1 ,4-dihydropyrrolo[3,2-b]pyridin-5-one; 244-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoro-methylpentyl] - ,5-dihydropyrrolo[3,2-c]pyridin-6-one; 2-[4-(5 -chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl[-5-methyl-1 ,5-dihydropyrrolo[3,2-c I pyridin-6-one; 4-(5-chloro-2,3-dihydrobenzofuran-7-yI)-I , 1, 1 -trifluoro-2-(6-methoxy-5,6-dihydro- 1 H-pyrrolo[3,2-c[pyridin-2-ylmethy1)-4-methylpentan-2-ol ; 244-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentylF 1 ,7-dihydropyrrolo[3,2-c[pyridine-4,6-dione; 644-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-3-tnethyl-1,7-dihydropyrrolo[2,3-d[pyrimidine-2,4-dione; 244-(3-dimethylaminomethylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll-IH-indole-5-carbonitrile; 1,1,1 -trifluoro-2-( 1 H-indo1-2-ylmethyl)-4-methyl-4-(3-morpholin-4-ylmethylphenyl)pentan-2-ol;
1,1, 1 -trifluoro-4-methy1-4-(3-morpholin-4-ylmethylpheny1)-2-(1H-pyrrolo[2- ,3-dlpyridazin-2-ylmethyppentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(5-morpholin-4-ylmethyl- 1H-indo1-2-ylmethyl)pentan-2-ol; 1, 1, 1 -trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-(5-morphol in-4-ylmethyl- 1H-pyrrolo[2,3-clpyridin-2-ylmethyl)pentan-2-ol; {244-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methyl -2-trifuoromethylpentyll- 1H-indo1-5-y1 } phenylmethanone; 2-[4-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty- 1]- I H-pyrrolo[2,3-c[pyridin-5-yllphenylmethanone; {214-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H-indo1-5-yllfuran-2-ylmethanone; { 244-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyli- 1H-pyrrolo[2,3-c]pyridin-5-y1 } furan-2-ylmethanone; 1,1, 1-trifluoro-2-( 1H-indo1-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol; 1 , I , 1 -trifluoro-4-methy1-4-pyridin-4-y1-2-quinolin-4-ylmethylpentan-2-ol; 2-(2,6-dimethylpyridin-4-ylmethyl)- 1 , 1 , 1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 243-(2,6-dimethylpyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy- 1, 1 -dimethylbuty11-4-fluorophenol; 1,1,1 -trifluoro-4,4-dimethy1-5-pheny1-2-quinolin-4-ylmethylpentan-2-ol; 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methyl-2-pyridin-4-ylmethylpentan-2-ol; 4-fluoro-244,4,4-trifluoro-3-(2-fluoropyridin-4-ylmethyl)-3-hydroxy- 1,1 -dimethylbutyllphenol; 243-(2-bromopyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy- 1,1 -dimethylbuty11-4-fluorophenol; 2-(6,8-dimethylquinolin-4-ylmethyl)- 1,1,1 -trifluoro-4-(5-fluoro-2-methoxy- phenyl)-4-methylpentan-2-ol; 414-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentylipyridine-2-carbonitrile;
2,6-dichloro-444-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyljnicotinonitrile; 414-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyllquinolin-2-ol; 2,6-dichloro-444-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]nicotinonitrile; 2-(2-chloro-8-methylquinolin-4-ylmethyl)- 1, 1, 1 -trifluoro-4-(5-fluoro-2-methoxyphenyI)-4-methylpentan-2-ol; 2-(2,6-dichloroquinolin-4-ylmethyl)- 1,1,1 -trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 243-(2-chloro-8-methylquinolin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-I, 1 -dimethylbuty1]-4-fluorophenol; 2-13-(2,6-dichloroquinolin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyli-4-fluorophenol;
dihydrobenzofuran-7-y1)-2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-methylpentan-2-ol; 2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-(3-fluoropheny1)-4-methylpentan-2-ol; 2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyI)-4-methylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methylpheny1)-4-methy1-2-quinolin-4-ylmethylpentan-2-ol; 2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methylpheny1)-4-methylpentan-2-ol; 2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-methy1-4-m-tolylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(2-methylquinolin-4-ylmethyl)pentan-2-ol; 4-fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1,1-dimethy1-3-quinolin-4-ylmethylbutyl)phenol; 4-fluoro-244,4,4-trifluoro-3-hydroxy-1,1-dimethy1-3-(2-methylquinolin-4-ylmethyl)butyl]phenol;
2-(2,6-dimethylpyridin-4-ylmethyl)-1,1,1-trifluoro-4-(4-fluoro-2-methoxypheny1)-4-methylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(7-methylquinolin-4-ylmethyl)pentan-2-ol; 243-(2,6-dimethylpyridin-4-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbuty1]-5-fluorophenol; and 2-(5,7-dimethylquinolin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxypheny1)-4-methylpentan-2-ol.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of CI-Cs alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, CI-Cs alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, CI-Cs alkylsulfonylamino, aminosulfonyl, Ci-Cs alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl;
(c) R3 is hydrogen, CI-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-Ci-C8 alkyl, carboxy, alkoxycarbonyl, aryl-C1-C8 alkyl, aryl-Ci-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-C1-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, C1-05 alkanoyl, aroyl, C1-Cs alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyloxy, C1-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-05 dialkylaminocarbonyl, Ci-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-Cs alkylsulfonylamino, Ci-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R3 cannot be trifluoromethyl;
(d) B is C1-05 alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(f) E is the hydroxy group; and (g) Q
comprises a heteroaryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, CI-Cs alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, CI-Cs alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, Ci-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, Ci-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, acyl, C1-C3 silanyloxy, C1-05 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or trifluoromethyl.
Non-limiting examples of these compounds include 2-cyclopropy1-4-(5-fluoro-2-methoxypheny1)-4-methyl-1-(1H-pyrrolof3,2-Opyridin-2-yppentan-2-ol; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-24 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentanoic acid; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentanoic acid methyl ester; 2-cyclopropy1-4-(5-fluoro-2-methylpheny1)-4-methyl- 1 -( I H-pyrrolo[2,3-c]pyridin-2-yOpentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-cyclopropy1-4-methyl- I -( 1 H-pyrrolo[2,3-c]pyridin-yl)pentan-2-ol ; 2-cyclopropy1-4-(5-fluoro-2-methylpheny1)-4-methyl-1-(1H-pyrrolo[3,2-cipyridin-2-yppentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-cyclopropy1-4-methyl- I -( 1 H-pyrrolo[3,2-Opyridin-2-yl)pentan-2-ol ; 4-(5-fluoro-2-methoxyphenyI)-2,4-dimethyl- 1 -( 1 H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol; 5-(5-fluoro-2-methoxypheny1)-2,5-dimethy1-3-( I H-pyrrolo[2,3-cipyridin-2-ylmethyphexan-3-ol; 5-(5-fluoro-2-methoxypheny1)-2,2,5-trimethy1-3-( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 2-cyclohexy1-4-(5-fluoro-2-methoxypheny1)-4-methyl-1-(1H-pyrrolo[2,3-clpyridin-2-y1)pentan-2-ol; 2-cyclopenty1-4-(5-fluoro-2-methoxypheny1)-4-methyl- 1 -(1H-pyrrolo[2,3-c]pyridin-2-yl)pentan-2-ol; 5-(5-fluoro-2-methoxypheny1)-5-methy1-3-( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 2-(5-fluoro-2-methoxypheny1)-2,6-dimethy1-4-( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethypheptan-4-ol; 2-(5-fluoro-2-methoxypheny1)-2,5,5-trimethy1-4-(1H-pyrrolo[2,3-c]pyridin-2-ylmethypheptan-4-ol; 1,1-difluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1 pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 1-cyclohexy1-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-( 1 H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol ;
5-(5-fluoro-2-methylpheny1)-2,5-dimethy1-3-(1H-pyrrolo[2,3-clpyridin-2-ylmethyphexan-3-ol; 5-(5-fuoro-2-methylphenyl- )-2,2,5-trimethy1-3-(1H-pyrrolo[2,3-clpyridin-2-ylmethyphexan-3-ol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,5-dimethy1-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 2-cyclobuty1-4-(5-fluoro-2-methoxypheny1)-4-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-y1)pentan-2-ol; 2-(5-fluoro-2-methoxypheny1)-2,6,6-trimethy1-4-(1H-pyrrolo[2,3-c]pyridin-2-ylmethypheptan-4-ol; 5-(5-fluoro-2-methoxypheny1)-5-methy1-3-(1H-pyrrolo[2,3-clpyridin-2-ylmethyl)hex-1-en-3-ol; 5-(5-fluoro-2-methoxypheny1)-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyphex-1-yn-3-ol; 1-fluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol; 2,2-difluoro-5-(5-fluoro-2-methoxypheny1)-5-methy1-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 2-fluoro-5-(5-fluoro-2-methoxypheny1)-2,5-dimethy1-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyphexan-3-ol; 2-fluoro-5-(5-fluoro-2-methoxypheny1)-5-methy1-3-(1H-pyrrolo[2,3-cipyridin-2-ylmethyl)hexan-3-ol; 5-(5-fluoro-2-methoxypheny1)-2,5-dimethy1-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hex-1-en-3-ol; 1,1,1-trifluoro-5-(5-fluoro-2-methoxypheny1)-5-methy1-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyphexan-3-ol;
4-(5-fluoro-2-methoxypheny1)-4-methy1-2-phenyl-1-(1H-pyrrolo[2,3-clpyridin-2-y1)pentan-2-ol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,2,5-trimethy1-3-(1H-pyrrolo[2,3-cjpyridin-2-ylmethyphexan-3-ol; 5-(5-fluoro-2-methylpheny1)-2,2,5-trimethyl-3-thieno[2,3-c]pyridin-2-ylmethylhexan-3-ol; 1,1-difluoro-4-(5-fluoro-2-methoxypheny1)-4-methy1-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol; 5-(5-fluoro-2-methoxypheny1)-2,5-dimethy1-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyphexan-3-01; 5-(5-fluoro-2-methoxypheny1)-2,2,5-trimethy1-3-(1H-pyrrolo[3,2-c]pyridin-ylmethyl)hexan-3-o!; 2-( 1 -fluorocyclopropy1)-4-(5-fluoro-2-methoxypheny1)-4-methyl -1 -( 1H-pyrrolo[2,3 -c[pyridin-2-yl)pentan-2-ol; 2-( 1 -fluorocyclopropy1)-4-(4-fluoropheny1)-4-methyl- I -quinolin-4-ylpentan-2-ol; 2-[4,4-difluoro-3-hydroxy-1 , 1 -dimethy1-3-( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethypbuty11-4-fluorophenol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,5-dimethy1-3-( 1 H-pyrrolo [3,2-c Ipyridin-2-. ylmethyl)hexan-3-ol; 5-(5-fluoro-2-methylpheny1)-2,5-dimethy1-3-( 1 H-pyrrolo[3,2-c] pyridin-2-y1 methyl)hexan-3-ol; 5-(5-fl uoro-2-methylpheny1)-2,2,5-trimethy1-3-( 1H-pyrrolo[3 ,2-c[pyridin-2-ylmethyl)hexan-3-ol ; 4-(5-chloro-2,3 -dihydrobenzofuran-7-y1)-1, 1 -difluoro-4-methyl-2-(1H-pyrrolo[3,2-c[pyridin-2-ylmethyl)pentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1 -difluoro-4-methyl-2-pyrrolo[3,2-b]pyridin- 1 -ylmethylpentan-2-ol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,2,5-trimethy1-3-( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyphexan-3-ol; 5-(5-fluoro-2-methylpheny1)-2,2,5-trimethy1-3 -(3-methyl- 1H-pyrrolo[2,3-clpyridin-2-ylmethyphex an-3 -ol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,5-dimethy1-3-(3-methy1-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 5-(5-chloro-2,3 -dihydrobenzofuran-7-y1)-2,5-dimethy1-3-(5-phenyl- 1H-pyrrolo[2,3-clpyridin-2-ylmethyl)hexan-3-ol; 5-(5-fluoro-2-methylpheny1)-2,2,5-trimethy1-3-(5-phenyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyphexan-3-ol; 5-(5-fluoro-2-methylpheny1)-2,5-dimethy1-3-(5-pheny1-1H-pyrrolo[2,3-c[pyridin-2-ylmethyl)hexan-3-ol; 5-(5-fluoro-2-methylpheny1)-5-methyl-3-(5-phenyl- 1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)hexan-3-ol; 4-(5-fluoro-2-methylpheny1)-2,4-dimethyl-1-(5-phenyl- 1 H-pyrrolo[2,3-clpyridin-2-yl)pentan-2-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)- 1,1 -difluoro-4-methyl-2-(6-methyl- 1H-pyrrolo[3,2-clpyridin-2-ylmethyl)pentan-2-ol; 5-(5-fluoro-2-methylpheny1)-2,5-dimethy1-3-(5-pyridin-3-yl- 1H-pyrrolo[2,3 -c[pyridin-2-ylmethyphexan-3 -01; 5 -(5-chloro-2,3 -dihydrobenzofuran-7-y1)-5-methy1-3-(5-phenyl- 1 H-pyrrolo[2,3-clpyridin-2-ylmethyl)hexan-3-ol; 4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,4-dimethyl- 1 -(5-phenyl- 1H-pyrrolo[2,3-clpyridin-2-yppentan-2-ol; 1,1 -difluoro-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-methy1-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyppentan-2-ol; 5-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2,5-dimethy1-3-(5-pyridin-3 -yl- 1H-pyrrolo[2,3 -clpyridin-2-ylmethyphexan-3-ol; 2-(5-bromo- 1H-indo1-2-ylmethyl)- 1 , 1 -difluoro-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methylpentan-2-ol; and 242-difluoromethy1-2-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methylpenty11-4-methyl- 1H-indole-6-carbonitrile.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, CI-Cs alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, Ci-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently C1-05 alkyl, wherein one or both are independently substituted with hydroxy, C1-05 alkoxy, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl;
(c) R3 is hydrogen, CI-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C1-C8 alkyl, carboxy, alkoxycarbonyl, aryl-Ci-C8 alkyl, aryl-C1-C8 haloalkyl, heterocyclyl-C1-C8 alkyl, heteroaryl-C1-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, Ci-05 alkoxy, phenoxy, C1-05 alkanoyl, aroyl, Ci-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyloxy, CI-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-05 dialkylaminocarbonyl, C1-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(d) B is C1-05 alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(0 E is the hydroxy group; and (g) Q comprises a heteroaryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, Ci-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, acyl, C1-C3 silanyloxy, C1-05 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or trifluoromethyl.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl, heteroaryl, heterocyclyl, or C3-C8 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen, C1-05 alkyl, C5-C15 arylalkyl, or RI and R2 together with the carbon atom they are commonly attached to form a C3-C8 Spiro cycloalkyl ring;
(c) B is the carbonyl group or methylene group, which is optionally independently substituted with one or two substituent groups selected from the group consisting of C1-C3 alkyl, hydroxy, and halogen;
(d) R3 is the trifluoromethyl group;
(e) D is absent;
(0 E is the hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl; and (g) Q comprises a 5- to 7-membered heterocyclyl ring fused to a 5-to 7-membered heteroaryl or heterocyclyl ring, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C1-05 alkyl, C2-Cs alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, Ci-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, acyl, aryl, benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, and ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl or trifluoromethyl, wherein Q cannot be 1H-[1,5]naphthyridin-4-one.
Non-limiting examples of these compounds include 4-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]-4H-thieno[3,2-1Apyridin-7-one; 444-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty- l]-4H-thieno[3,2-b]pyridin-7-one; 444-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1J-4H-thieno[3,2-b]pyridin-7-one; 114-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyll- 1H-[ 1 ,6]naphthyridin-4-one; 1 44-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentylF I H-[1,61naphthyridin-4-one; 444-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl[-4H-thieno[3,2-b[pyridin-7-one; 442-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methyl-2-trifluoromethylpenty1]-thieno[3,2-b]pyridin-7-one; 142-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpentyli -1 H-[ 1 ,6]naphthyridin-4-one; I 14-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifl uoromethylpenty1]- 1 H-[ 1,6]
naphthyridin-4-one; 442-hydroxy-4-(2-methoxy-3-methylpheny1)-4-methyl-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 442-hydroxy-4-(2-methoxypheny1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 444-(3-bromo-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 442-hydroxy-4-(2-hydroxy-3-methylpheny1)-4-methyl-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 444-(3-bromo-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 3-bromo-144-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-[1,6]naphthyridin-4-one; 6-chloro-444-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 6-bromo-4-[4-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 3-chloro-114-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11- 1 H-[ 1,6]naphthyridin-4-one; 1 -[4-(5-chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-3 -methyl-[1,6]naphthyridin-4-one; 144-(5-Chloro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-3-methy1-1H-[1,7]naphthyridin-4-one; 1-[2-hydroxy-4-(2-methoxy-3 ,5-dimethy lpheny1)-4-methyl-2-trifluoromethy lpentyl] -3 -methyl-[1,6]naphthyridin-4-one; 1 42-hydroxy-4-(2-methoxy-3,5-dimethylpheny1)-4-methy1-2-trifluoromethylpenty1]-3-methyl-1H41,7]naphthyridin-4-one; 142-hydroxy-4-(2-hydroxy-3,5-dimethylpheny1)-4-methy1-2-trifluoromethylpenty1]-3-methy1-1H-[1,6]naphthyridin-4-one; 1 44-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-[1,8]naphthyridin-4-one; 144-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-1H41,7]naphthyridin-4-one; 4-[4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty- 1]-4H-thiazolo[4,5-b]pyridin-7-one; 4-14-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-4H-oxazolo[4,5-b]pyridin-7-one; 444-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-4H-furo[3,2-b]pyridin-7-one; 7-[4-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-7H-thieno[2,3-b]pyridin-4-one; 444-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-4H-oxazolo[5,4-b]pyridin-7-one; 444-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty11-4H-thiazolo[5,4-b]pyridin-7-one; 744-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyl]-7H-furo[2,3-b]pyridin-4-one; 444-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll- I ,4-dihydropyrrolo[3,2-blpyridin-7-one; 1 -[4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-5,6,7,8-tetrahydro- 1 H-[1 ,6]naphthyridin-4-one; 1 14-(5-fluoro-2-methylpheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-6-methy1-5,6,7,8-tetrahydro- 1 H-[ 1 ,6]naphthyridin-4-one; 1 44-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpentyll 1 H-[ 1,81naphthyridin-4-one; 1-[2-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]-1H-[1,7]naphthyridin-4-one;
4- [2-hydroxy-4-(5-methane sulfony1-2,3 -dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]-4- H-thiazolo[4,5-b]pyridin-7-one; 444-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-4H-oxazolo[4,5-blpyridin-7-one; 4-[2-hydroxy-4-(5 -methanesulfony1-2,3 -dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]-4H-furo[3,2-blpyridin-7-one; 744-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-7H-thieno[2,3-blpyridin-4-one; 442-hydroxy-4-(5-methanesulfony1-2,3 -dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]-4H-oxazolo[5,4-b]pyridin-7-one; 442-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty11-thiazolo[5,4-b]pyridin-7-one; 744-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-7H-furo[2,3-b]pyridin-4-one; 444-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]- 1 ,4-dihydropyrrolo[3,2-b]pyridin-7-one; 1 -[2-hydroxy-4-(5-methanesulfony1-2,3-dihydrobenzofuran-7-y1)-4-methy1-2-trifluoromethylpenty1]-5,6,7,8-tetrahydro- 1H-[ I ,6]naphthyridin-4-one; 1 4442,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-tTifluoromethylpentyl]-6-methyl-5,6,7,8-tetrahydro- 1 H-[ 1,6]naphthyridin-4-one; 1-[4-(2,3-dihydrobenzofuran-7-y1)-2-hydrox y-4-methy1-2-trifluoromethylpenty1]-5-methyl-5,6,7,8-tetrahydro- 1H-[ 1 ,5]naphthyridin-4-one; 1 44-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-5-methy1-5,6,7,8-tetrahydro- 1 H-[ 1 ,5 inaphthyridin-4-one; 4-[2-hydroxy-4-(4-methoxybipheny1-3-y1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 412-hydroxy-4-(2-methoxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpenty11-4H-thieno[3,2-b]pyridin-7-one; 4-[2-hydroxy-4-(2-methoxy-5-pyrimidin-5-ylpheny1)-4-methy1-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 442-hydroxy-4-(2-methoxy-5-thiophen-3-ylpheny1)-4-methy1-2-trifluoromethylpenty11-4H-thieno[3,2-b]pyridin-7-one; 442-hydroxy-4-(4-hydroxybipheny1-3-y1)-4-methy1-2-trifluoromethylpenty11-4H-thieno[3,2-b]pyridin-7-one; 412-hydroxy-4-(2-hydroxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 442-hydroxy-4-(2-hydroxy-, pyrimidin-5-ylpheny1)-4-methy1-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 442-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylpheny1)-4-methyl-2-trifluoromethylpentyl]-4H-thieno[3,2-b]pyridin-7-one; 142-hydroxy-4-(4-methoxybipheny1-3-y1)-4-methyl-2-trifluoromethylpenty11-1H-[1,6]naphthyridin-4-one;
1-[2-hydroxy-4-(2-methoxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpentyl]-1H-[1,6]naphthyridin-4-one; 142-hydroxy-4-(2-methoxy-5-pyrimidin-5-ylpheny1)-4-methy1-2-trifluoromethylpenty1]- 1H- [ 1,6]naphthyridin-4-one; I 42-hydrox y-4-(2-methoxy-5-thiophen-3-ylpheny1)-4-methy1-2-trifluoromethylpentyl]-1H-[ 1,6]naphthyridin-4-one- ; 1 42-hydroxy-4-(2-methoxy-5-thiophen-3-ylpheny1)-4-methy1-2-trifluoromethylpenty11- 1H-[1,6]naphthyridin-4-one; 112-hydroxy-4-(2-hydroxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpenty11- 1 H-[
1,6]naphthyridin-4-one; 142-hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylpheny1)-4-methy1-2-trifluoromethylpenty11-1H-[1,6]naphthyridin-4-one; 142-hydroxy-4-(2-hydroxy-5-thiophen-3-ypheny1)-4-methyl-2-trifluoromethylpenty11-1H-[1,6]naphthyridin-4-one; 5-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]-5H-pyrido[3,2-d]pyrimidin-8-one; 1-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]-1H-pyrido[2,3-dlpyridazin-4-one; 5-[4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-trifluoromethylpenty- 1]-5H-pyrido[3,2-c]pyridazin-8-one; 444-(2-fifluoromethoxy-3-methylphenyl- )-2-hydroxy-4-methy1-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 3-chloro-114-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]- 1 H-[1,6]naphthyridin-4-one; 4-(4-benzo[1,3]dioxo1-4-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-6-bromo-4H-thieno[3,2-b]pyridin-7-one; 4-(4-benzo[ 1,3 Idioxo1-4-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-6-chloro-4H-thieno[3,2-b]pyridin-7-one; 6-chloro-442-hydroxy-4-methy1-4-(5-pyridin-3-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]-4H-thieno[3,2-blpyridin-7-one; 1-(4-benzo[1,3]dioxo1-4-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-3-chloro-1H-[1,6]naphthyridin-4-one;

chloro-4-[2-hydroxy-4-methy1-4-(5-pyrimidin-5-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 3-chloro- 1 -[2-hydroxy-4-methy1-4-(5-pyrimidin-5-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]- 1 H-[ 1 ,6}naphthyridin-4-one; 3-chloro- 1 42-hydroxy-4-methy1-4-(5-pyridin-3-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpentyll- 1 H-[ 1 ,6]naphthyridin-4-one; 4-[2-hydroxy-4-methy1-4-(5-pyrimidin-5-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 1 -[2-hydroxy-4-methy1-4-(5-pyrimidin-5-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]- 1H-[ 1,61naphthyridin-4-one; 6-chloro-442-hydroxy-4-(2-methoxy-5-pyridin-3-ylpheny1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 6-chloro-442-hydroxy-4-(2-methoxy-5-pyrimidin-5-ylpheny1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 6-chloro-412-hydroxy-4-(2-hydroxy-5-pyridin-3-ylpheny1)-4-methyl-2-trifluoromethylpenty11-4H-thieno[3,2-blpyridin-7-one; 6-chloro-4-[2-hydroxy-4-(- 2-hydroxy-5-pyrimidin-5 -ylpheny1)-4-methyl-2-trifluoromethylpentyl] -4H-thieno[3,2-b]pyridin-7-one ; 4-(4-bipheny1-3-y1-2-hydroxy-4-methy1-2-trifluoro-methylpenty1)-6-chloro-4H-thieno[3,2-b]pyridin-7-one; 4-(4-bipheny1-3-y1-2-hydroxy-4-methy1-2-trifluoromethylpenty1)-4H-thieno[- 3,2-b]pyridin-7-one; 3-chloro-1-{4-[5-(5-chloropyridin-3-y1)-2,3-dihydrobenzofuran-7-y1]-2-hydroxy-4-methy1-2-trifluoromethylpentyl -1H-11 ,61naphthyridin-4-one; 6-chloro-4- 44542,6-dimethylpyridin-4-y1)-2-methoxypheny1]-2-hydroxy-4-methy1-2-trifluoromethylpentyll -4H-thieno[3,2-b]pyridin-7-one- ; 442-hydroxy-4-(2-hydroxy-5-pyridin-2-ylpheny1)-4-methy1-2-trifluoromethylpenty1]-4H-thieno[3 ,2-blpyridin-7-one; 6-chloro-442-hydroxy-4-methy1-4-(5-pyrazin-2-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1]-4H-thieno[3,2-b]pyridin-7-one; 3-chloro- I -[2-hydroxy-4-methy1-4-(5-pyrimidin-2-y1-2,3-dihydrobenzofuran-7-y1)-2-trifi uoromethylpenty1]- 1H-I 1 ,6]naphthyridin-4-one; 5-{ 743 -(6-chloro-7-oxo-7H-thieno[3,2-b]pyridin-4-ylmethyl)-4,4,- 4-trifluoro-3-hydroxy- I , I -dimethylbuty11-2,3-dihydrobenzofuran-5-yll nicotinonitrile; 4- { 4-Methoxy-344,4,4-trifluoro-3-hydroxy- 1, 1 -dimethy1-3-(7-oxo-7H-thieno[3,2-b]pyridin-4-ylmethyl)butyl]phenyl }pyridine-2-carbonitrile; 6-chloro-4-{ 445-(2-fluoro-6-methylpyridin-4-y1)-2-methoxypheny1]-2-hydroxy-4-methy1-2-trifluoromethylpentyl } -4H-thieno[3,2-b]pyridin-7-one; 3-chloro- 1 - 2-hydroxy-4[5-( 1 H-imidazol-4-y1)-2,3-dihydrobenzofuran-7-y1]-4-methyl-2-trifluoromethylpentyl } - IH-[ 1 ,6]naphthyridin-4-one; 6-chloro-412-hydroxy-4-methy1-4-(5-morpholin-4-y1-2,3-dihydrobenzofuran-7-y1)-2-trifluoromethylpenty1F4H-thieno[3,2-blpyridin-7-one; and 142-hydroxy-4-methy1-4-(5-piperidin- 1 -y1-2,3 -dihydrobenzofuran-7-y1)-2-trifluoromethylpentyll- 1 H-[1,61naphthyridin-4-one.
In yet another embodiment, said at least a DIGIVi has Formula I, wherein A, B, D, E, RI, and R2 have the meanings disclosed immediately above, and R3 is hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-Ci-C8 alkyl, carboxy, alkoxycarbonyl, aryl-Ci-C8 alkyl, aryl-Ci-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-Ci-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-Cs alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, C1-05 alkanoyl, aroyl, C1-05 alkoxycarbonyl, Ci-05 alkanoyloxy, aminocarbonyloxy, CI-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-05 dialkylaminocarbonyl, Ci-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, Ci-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with CI-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R3 cannot be trifluoromethyl.
In yet another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl, heteroaryl, heterocyclyl, or C3-C8 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, Ci-alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio where,in the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl;
(c) R3 is the trifluoromethyl group;
(d) B is Ci-05 alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
(f) E is the hydroxy group; and (g) Q comprises an indolyl group optionally substituted with one to three substituent groups, wherein each substituent group of Q is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C5 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1 -05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, or C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, oxo, cyano, amino, and trifluoromethyl.
Non-limiting examples of these compounds include 4-(5-bromo-2,3-di hydrobenzofuran-7-y1)- 1,1,1 -trifluoro-2-( 1 H-indo1-2-ylmethyl)-4-methylpentan-2-ol;
1,1,1-trifluoro-2-(1H-indo1-2-ylmethyl)-4-methyl-4-pyridin-2-ylpentan-2-ol; 4-(2,3-dihydro-5-cyanobenzofuran-7-y1)-1,1,1-trifluoro-2-(1H-indo1-2-yl-methyl)-4-methylpentan-2-ol; 4-(2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-2-(1H-indo1-ylmethyl)-4-methylpentan-2-ol; 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-( 1 H-indo1-2-ylmethyl)-4-methylpentan-2-ol; 1, 1, 1 -trifluoro-2-( 1 H-indo1-2-ylmethyl)-4-methy1-4-(5-methy1-2,3-dihydrobenzofuran-7-yOpentan-2-ol ; 4-(2,3-dihydrobenzofuran-5-y1)-1,1,1-trifluoro-2-(1H-indo1-2-ylmethyl)-4-methylpentan-2-ol;
2-14-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-indole-3-carbonitrile; 2-14-(5-fluoro-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methyl-2-trifluoromethylpenty1]- 1 H-indole-3-carbonitrile; 244-(5-bromo-2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty11-1H-indole-3-carbonitrile;
24442,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-4-methyl-indole-6-carbonitrile; 244-(2,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indole-5-carbonitrile; 4-(2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-2-(7-fluoro- 1 H-indo1-2-ylmethy1)4-methylpentan-2-ol ; 1 4442,3-dihydrobenzofuran-7-y1)-2-hydroxy-4-methy1-2-trifluoromethylpenty1]-1H-indole-carbonitrile; 4-(2,3-dihydrobenzofuran-7-y1)-1,1,1-trifluoro-4-methy1-2-(5-trifluoromet-hy1-1H-indo1-2-ylmethyl)pentan-2-ol; and 1,1,1-trifluoro-2-(1H-indo1-2-ylmethyl)-4-methyl-4-thiophen-3-ylpentan-2-ol.
In a further embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, Ci-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, C1-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-k5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl, or RI and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;
(c) R3 is carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-CI-C8 alkyl, carboxy, alkoxycarbonyl, aryl-Ci-C8 alkyl, aryl-C1-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-C1-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C 1 -C5 alkoxy, phenoxy, C1-05 alkanoyl, aroyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyloxy, Ci-05 alkylaminocarbonyloxy, Ci-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, C1-05 dialkylaminocarbonyl, C1-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1-05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(d) B is the methylene or carbonyl group;
(e) D is the ¨NH- group;
(f) E is the hydroxy group; and (g) Q comprises the group =0 Non-limiting examples of these compounds include 2-benzy1-2-hydroxy-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-4-methy1-2,4-diphenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yDamide; 2-hydroxy-4-methyl-2-phenethy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-2-(3-methoxybenzy1)4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-2-(4-methoxybenzy1)-4-methy1-4-phenylpentanoic acid ( 1 -oxo- 1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-242-(4-methoxyphenypethy114-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-cyclohexylmethy1-2-hydroxy-4-methy1-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(4-tert-butylbenzy1)-2-hydroxy-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-bipheny1-4-ylmethy1-2-hydroxy-4-methyl-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-4-methy1-2-naphthalen-2-ylmethy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-2-(3-hydroxybenzy1)-4-methy1-4-phenylpentanoic acid (1-oxo- 1, 3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-4-methy1-2-(2-methy1-2-phenylpropy1)-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-benzy1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-cyclohexylmethy1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-benzy1-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-cyclohexylmethy1-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-(2-methy1-2-phenylpropyppentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide;
2-(2-chloro-6-fluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3-fluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1 -oxo-1 ,3-dihydroisobenzofuran-5-yl)amide; 2-(2-fluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,4-difluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo- 1 ,3-dihydroisobenzofuran-5-yl)amide; 2-(2-chloro-6-fluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (I -oxo- 1,3-dihydroisobenzofuran-5-yl)amide; 2-(3-fluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2-fluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,4-difluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(4-fluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1 ,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-(3-methylbenzyl)pentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide;
2-(4-fluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-(3-methylbenzyl)pentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide;
2-(3,5-difluoropheny1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-(2-methylbenzyl)pentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,5-dimethylbenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2,5-difluorobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2,5-difluorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-(2-methylbenzyppentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,5-dimethylbenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3-chlorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-2-12-(4-methoxyphenyl)ethyl]-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-2-(2-methoxybenzy1)4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-phenethylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2-chlorobenzyl)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-phenethylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide;

fluoro-2-hydroxypheny1)-2-hydroxy-242-(4-hydroxyphenypethyl]-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2-chlorobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-2-(2-hydroxybenzy1)-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2-bromobenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(2-bromobenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(5-fluoro-2-methoxybenzy1)-2-hydroxy-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(5-fluoro-2-hydroxybenzy1)-2-hydroxy-4-methy1-4-phenylpentanoic acid (I-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(5-fluoro-2-methoxybenzy1)-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(5-fluoro-2-hydroxybenzy1)-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,5-dimethoxybenzy1)-2-hydroxy-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-(3,5-dihydroxybenzy1)-2-hydroxy-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-y1)- amide; 2-hydroxy-2-(2-methoxybenzy1)4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-y0amide; 12-hydroxy-2-(2-hydroxybenzy1)-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-242-(4-hydroxyphenypethy11-4-methy1-4-phenylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 1542-benzy1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentylamino]-3H-isobenzofuran-1-one ; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methy1-2-(1-phenylvinyl)pentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-hydroxy-4-methy1-4-pheny1-2-pyridin-2-ylmethylpentanoic acid (I-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methyl-2-( 1 -phenylethyl-)pentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methy1-2-( 1 -phenylethyl)pentanoic acid (I -oxo- 1 ,3-dihydroisobenzofuran-5-yl)amide; 2-cyclopenty1-4-(5-fluoro-2-methoxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-cyclopenty1-4-(5-fluoro-2-hydroxypheny1)-2,hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; 2-cyclopentylmethy1-4-(5-fluoro-2-hydroxypheny1)-2-hydroxy-4-methylpentanoic acid (1-oxo-1,3-dihydroisobenzofuran-5-yl)amide; and 2-benzy1-2-hydroxy-N-(1-oxo-1,3-dihydroisobenzofuran-5-y1)4-phenyl-butyramide.
In still another embodiment, said at least a DIGRA has Formula I, wherein (a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C1-C3 alkanoyl, C3-Cs cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-alkynyloxy, aryloxy, acyl, C1-05 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, C1-05 dialkylaminocarbonyloxy, C1-05 alkanoylamino, Ci-alkoxycarbonylamino, C1-05 alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaninosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, Ci-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;
(b) RI and R2 are each independently hydrogen or C1-05 alkyl, or RI and R2 together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring;
(c) R3 is the trifluoromethyl group;

(d) B is CI-Cs alkylene, C2-05 alkenylene, or C2-05 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C1-C3 alkyl, hydroxy, halogen, amino, or oxo;
(e) D is absent;
E is ¨NR6R7, wherein R6 and R7 are each independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl, carbocycle-Ci-C8 alkyl, aryl-Ci-C8 alkyl, aryl-Ci-C8 haloalkyl, heterocyclyl-Ci-C8 alkyl, heteroaryl-Ci-Cs alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-C8 alkenyl, heterocyclyl-C2-C8 alkenyl, heteroaryl-C2-C8 alkenyl, or CI-Cs alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R6 and R7 are independently CI-Cs alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, C1-Cs alkanoyl, aroyl, CI-Cs alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyl, CI-Cs alkylaminocarbonyl, CI-Cs dialkylaminocarbonyl, aminocarbonyloxy, CI-Cs alkylaminocarbonyloxy, CI-Cs dialkylaminocarbonyloxy, C1-Cs alkanoylamino, Ci-alkoxycarbonylamino, C1-Cs alkylsulfonylamino, aminosulfonyl, C1-05 alkylaminosulfonyl, C1-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with CI-Cs alkyl, or CI-Cs alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and (g) Q comprises a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C1-C5 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-05 alkoxy, C2-05 alkenyloxy, C2-05 alkynyloxy, aryloxy, acyl, CI-Cs alkoxycarbonyl, CI-Cs alkanoyloxy, aminocarbonyl, CI-Cs alkylaminocarbonyl, CI-05 dialkylaminocarbonyl, aminocarbonyloxy, CI-Cs alkylaminocarbonyloxy, CI-Cs dialkylaminocarbonyloxy, Ci-05 alkanoylamino, CI-Cs alkoxycarbonylamino, CI-Cs alkylsulfonylamino, aminosulfonyl, Ci-05 alkylaminosulfonyl, CI-Cs dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by CI-05 alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl;
or C1-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl.
Non-limiting examples of these compounds include 3-(5-fluoro-2-methoxy-pheny1)-3-methyl- 1 -(pyridin-2-ylmethyl)- 1 -trifluoromethyl-butylamine; 3-(5-fluoro-2-methoxy-pheny1)-1-(1H-indo1-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine;

(2,6-dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-3 -methyl- 1 -trifluoromethyl-butylamine; 1-(4,6-dimethyl-pyridin-2-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-3-methyl-l-trifluoromethyl-butylamine; 1-(2-chloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-3-methyl-1-trifluoromethyl-butylamine;
3-(5-fluoro-2-methyl-pheny1)-3-methy1-1-(3-methyl-1H-indo1-2-ylmethyl)-1-trifluoromethyl-butylamine; 3-(5-fluoro-2-methoxy-phenyl)-3 -methyl-1 -(3-methyl-1 H-indo1-2-ylmethyl)-1-trifluoromethyl-butylamine; 1-(6-fluoro-1H-indo1-2-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-3-methyl-1-trifluoromethyl-butylamine; 3-(4-fluoro-pheny1)-3-methyl-1 -(3-methyl- 1H-indo1-2-ylmethyl)- 1 -trifluoro-methyl-butylamine; 3 -benzofuran-'7-y1-1 -(2,6-dichloro-pyridin-4-ylmethyl)-3-methy1-1 -trifluoromethyl-butylamine; 3-(2,3-dihydro-benzofuran-7-y1)- 1 -(6-fluoro- 1H-indo1-2-ylmethyl)-3-methyl- 1 -trifluoromethyl-butylamine; 3-(5-fluoro-2-methoxy-phenyl)-3 -methyl-1 -quinolin-4-ylmethyl- 1 -trifluoromethyl-butylamine; 1-(2-chloro-quinolin-4-ylmethyl)-3-(5-fluoro-2-methyl-pheny1)-3-methyl- 1 -trifluoromethyl-butylamine; 3-(4-fluoro-phenyl)-3 -methyl-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine; 7-[3-amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1 , 1 -dimethyl-buty1]-2,3-dihydrobenzofuran-5-carbonitrile; 1 -(6-fluoro-1 H-benzoimidazol-2-ylmethyl)-3 -(5 -fluoro-2-methyl-pheny1)-3 -methyl-1 -trifluoromethyl-butylamine; 243-amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro- 1, 1 -dimethyl-butyl[4-fluoro-phenol; 1 -(1H-benzoimidazol-2-ylmethyl)-3-(4-fluoro-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(1H-indo1-2-ylmethyl)-3-meth-y1-3-pyridin-3-yl- 1-trifluoromethyl-butylamine; 1-( 1H-benzoimidazol-2-ylmethyl)-3-methy1-3-pyridin-4-y!- 1 -trifluoromethyl-butylamine; 3-methyl-I -(3-methyl-1 H-indo1-2-ylmethyl)-3-pyridin-3-yl- 1 -trifluoromethyl-butylamine; 1 -(6-fluoro- 1 H-indo1-2-yl methyl)-3-methy1-3-pyridin-3-y1-1-trifluoromethyl-butylamine; 3-(2,3-dihydro-benzofuran-7-y1)- 1 -( 1 H-indo1-2-ylmethyl)-3-methyl- 1 -trifluoromethyl-butylamine; [3-(5-fluoro-2-methoxy-pheny1)-3 -methyl- 1 -quinolin-4-ylmethyl- 1 -trifluoromethyl-butyll-methyl-amine; ethy113-(5-fluoro-2-methoxy-pheny1)-3-methyl-,1-quinolin-4-ylmethyl- 1 -trifluoromethyl-buty11-amine; [3-(5-fluoro-2-methoxy-pheny1)-3-methy1-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl[-propylamine; [3-(5-fluoro-2-methoxy-pheny1)-methyl- 1 -quinolin-4-ylmethyl- 1 -trifluoromethyl-buty11-isobutylamine; butyl-[3-(5-fluoro-2-methoxy-pheny1)-3 -methyl-1 -quinolin-4-ylmethy1-1 -trifluoromethyl-butyl] -amine; [3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1 -quinolin-4-ylmethyl- 1 -trifluoro-methyl-butyl]-dimethylamine; N13-(5-fluoro-2-methoxy-pheny1)-3-methyl-1-quinolin-4-ylmethyl- 1 -trifluoromethyl-butyl] -acetam ide; N43-(5-fluoro-2-methoxy-pheny1)-3-methyl- 1 -quinolin-4-ylmethyl- 1 -trifluoromethyl-butyl]formamide; N43-(5-fluoro-2-methoxy-pheny1)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methanesulfonamide; 1-(2,6-dimethyl-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-3 -methyl-1 -trifluoromethyl-butylamine; 3 -(5-fluoro-2-methoxy-phenyl)-3 -methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1-trifluoromethyl-butylamine;

amino-4-(5-fluoro-2-methoxy-pheny1)-4-methy1-2-trifluoromethyl-penty1]-4-methyl- 1 H-indole-6-carbonitrile; N-[3-(5-fluoro-2-methoxy-pheny1)-3-methyl-l-quinolin-4-ylmethyl-1-trifluoromethyl-buty1]-hydroxylamine; and 2-(3-amino-4,4,4-trifluoro-1,1-dimethy1-3-quinolin-4-ylmethyl-buty1)-4-fluoro-phenol.
In yet another embodiment, said at least a DIGRA has Formula I, wherein A, B, D, E, RI, R2, R6, and R7 have the meanings disclosed immediately above, and R3 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C1-C8 alkyl, carboxy, alkoxycarbonyl, aryl-C1-C8 alkyl, aryl-C/-C8 haloalkyl, heterocyclyl-C1-C8 alkyl, heteroaryl-Ci-C8 alkyl, carbocycle-C2-C8 alkenyl, aryl-C2-Cs alkenyl, heterocyclyl-C2-C8 alkenyl, or heteroaryl-C2-C8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R3 is independently C1-05 alkyl, C2-05 alkenyl, C2-05 alkynyl, C3-C8 cycloalkyl, phenyl, C1-05 alkoxy, phenoxy, Ci-05 alkanoyl, aroyl, C1-05 alkoxycarbonyl, C1-05 alkanoyloxy, aminocarbonyloxy, C1-05 alkylaminocarbonyloxy, Ci-05 dialkylaminocarbonyloxy, aminocarbonyl, C1-05 alkylaminocarbonyl, Ci-05 dialkylaminocarbonyl, C1-05 alkanoylamino, C1-05 alkoxycarbonylamino, C1 -05 alkylsulfonylamino, C1-05 alkylaminosulfonyl, Ci-05 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-05 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C1-05 alkyl, CI-05 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R3 cannot be trifluoromethyl.
Non-limiting examples of these compounds include 1-(2,6-dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-pheny1)-1,3-dimethyl-butylamine; 1-ethyl-3-(5-fluoro-2-methoxy-pheny1)-3-methy1-1-quinolin-4-ylmethyl-butylamine; 1-cyclohexylmethy1-3-(5-fluoro-2-methoxy-pheny1)-1-(1H-indo1-2-ylmethyl)-3-methyl-butylamine; 1-(2-chloro-quinolin-4-ylmethyl)-1-cyclopenty1-3-(5-fluoro-2-methoxy-pheny1)-3-methyl-butylamine; 1-(2-chloro-pyriclin-4-ylmethyl)-1-cyclopentylmethy1-3-(5-fluoro-2-methoxy-pheny1)-3-methyl-butylamine; 3-(5-fluoro-2-methoxy-pheny1)-1,3-dimethy1-1-quinolin-4-ylmethyl-butylamine; 1-cyclopropy1-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-l-quinolin-4-ylmethyl-butylamine; 3-(5-fluoro-2-methoxy-pheny1)-1,3-dimethyl-1-(1H-pyrrolo12,3-c]pyridin-2-ylmethyl)-butylamine; 1-cyclopropy1-3-(5-fluoro-methoxy-pheny1)-3-methyl-1-(1H-pyrrolof2,3-0-pyridin-2-ylmethyl)-butylamine;

amino-1,1,3-trimethy1-4-(1H-pyrrolo[2,3-cipyridin-2-y1)-butyl)-4-fluoro-phenol; 242-amino-4-(5-fluoro-2-methoxy-pheny1)-2,4-dimethyl-penty11-4-methyl-1H-indole-6-carbonitrile.
Other compounds that can function as DIGRAs and methods for their manufacture are disclosed, for example, in U.S. Patent Application Publications 2004/0029932, 2004/0162321, 2004/0224992, 2005/0059714, 2005/0176706, 2005/0203128, 2005/0234091, 2005/0282881, 2006/0014787, 2006/0030561, and 2006/0116396.
In another aspect, the present invention provides an ophthalmic pharmaceutical composition for treating or alleviating a dry eye condition or other ophthalmic disorders, which require rewetting of the eye. The ophthalmic pharmaceutical composition comprises at least a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof. In one aspect, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
The concentration of a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof in such an ophthalmic composition can be in the range from about 0.001 to about 1000 mg/ml (or, alternatively, from about 0.001 to about 500 mg/ml, or from about 0.01 to about 300 mg/ml, or from about 0.1 to about 250 mg/ml, or from about 0.1 to about 100 mg/ml).
In one embodiment, a composition of the present invention is in a form of a suspension or dispersion. In another embodiment, the suspension or dispersion is based on an aqueous solution. For example, a composition of the present invention can comprise sterile saline solution. In still another embodiment, micrometer- or nanometer-sized particles of a DIGRA, or prodrug thereof, or a pharmaceutically acceptable salt thereof can be coated with a physiologically acceptable surfactant (non-limiting examples are disclosed below), then the coated particles are dispersed in an liquid medium. The coating can keep the particles in a suspension.
In another aspect, a composition of the present invention can further comprise a non-ionic surfactant, such as polysorbates (such as polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), commonly known by their trade names of Tween 80, Tween 60, Tween 20), poloxamers (synthetic block polymers of ethylene oxide and propylene oxide, such as those commonly known by their trade names of Plutonic(); e.g., Plutonic F127 or Plutonic F108) ), or poloxamines (synthetic block polymers of ethylene oxide and propylene oxide attached to ethylene diamine, such as those commonly known by their trade names of Tetronic ; e.g., Tetronic 1508 or Tetronic 908, etc., other nonionic surfactants such as Brij , Myrj , and long chain fatty alcohols (i.e., oleyl alcohol, stearyl alcohol, myristyl alcohol, docosohexanoyl alcohol, etc.) with carbon chains having about 12 or more carbon atoms (e.g., such as from about 12 to about 24 carbon atoms). Such compounds are delineated in Martindale, 34th ed., pp 1411-1416 (Martindale, "The Complete Drug Reference," S.

C. Sweetman (Ed.), Pharmaceutical Press, London, 2005) and in Remington, "The Science and Practice of Pharmacy," 2first Ed., p. 291 and the contents of chapter 22, Lippincott Williams & Wilkins, New York, 2006) . The concentration of a non-ionic surfactant, when present, in a composition of the present invention can be in the range from about 0.001 to about 5 weight percent (or alternatively, from about 0.01 to about 4, or from about 0.01 to about 2, or from about 0.01 to about 1 weight percent).
In addition, a composition of the present invention can include additives such as buffers, diluents, carriers, adjuvants, or excipients. Any pharmacologically acceptable buffer suitable for application to the eye may be used. Other agents may be employed in the composition for a variety of purposes. For example, buffering agents, preservatives, co-solvents, oils, humectants, emollients, stabilizers, or antioxidants may be employed.
Water-soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, ethyl alcohol, methylparaben, polyvinyl alcohol, benzyl alcohol, and phenylethyl alcohol.
These agents may be present in individual amounts of from about 0.001 to about 5% by weight (preferably, about 0.01% to about 2% by weight). Suitable water-soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the United States Food and Drug Administration ("US FDA") for the desired route of administration.
These agents may be present in amounts sufficient to maintain a pH of the system of between about 2 and about 11. As such the buffering agent may be as much as about 5%
on a weight to weight basis of the total composition. Electrolytes such as, but not limited to, sodium chloride and potassium chloride may also be included in the formulation.
In one aspect, the pH of the composition is in the range from about 4.5 to about II. Alternatively, the pH of the composition is in the range from about 6 to about 9, or from about 6.5 to about 8. In another aspect, the composition comprises a buffer having a pH in one of said pH ranges.
In another aspect, the composition has a pH of about 7. Alternatively, the composition has a pH in a range from about 7 to about 7.5.

In still another aspect, the composition has a pH of about 7.4.
In a further aspect, a composition of the present invention formulated for the treatment of dry eye-type diseases and disorders may also comprise carriers designed to provide immediate, short-term relief of dry eye-type conditions. Such carriers can be formulated as a phospholipid carriFr or an artificial tears carrier, or mixtures of both. A
phospholipid carrier comprises one or more phospholipids that lubricate, wet, approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration. Non-limiting examples of phospholipid carrier formulations include those disclosed in U.S. Patents 4,804,539; 4,883,658; 4,914,088; 5,075,104;
5,278,151;
5,294,607; 5,371,108; 5,578,586.
In yet another aspect, a composition also can comprise a viscosity-modifying compound designed to lubricate, wet, approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration the eye. Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol; various polymers of the cellulose family, such as hydroxypropylmethyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") sodium, hydroxypropyl cellulose ("HPC"); polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, such as, dextran 70; water soluble proteins, such as gelatin; vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone; carbomers, such as carbomer 934P, carbomer 941, carbomer 940, or carbomer 974P; and acrylic acid polymers. In general, a desired viscosity can be in the range from about 1 to about 400 centipoises ("cps").
In yet another aspect, the present invention provides a composition for treating or alleviating the dry eye condition or an ophthalmic disorder requiring rewetting of the eye. The composition comprises: (a) at least a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) an immunosuppressive medicament;
said DIGRA, prodrug thereof, or pharmaceutically acceptable salt thereof, and immunosuppressant medicament being present in amounts effective to treat or alleviate said dry eye condition or ophthalmic disorder. In one embodiment, such an immunosuppressive medicament comprises Cyclosporine, such as for example Cyclosporine A. The concentration of Cyclosporine in such a composition can range from about 0.01 to about 2 percent by weight, or from about 0.1 to about 1.5 percent by weight, or from about 0.2 to about 1 percent by weight. Other immunosuppressive medicaments also can be suitable, such as Azathioprine, Cyclophosphamide, Tacrolimus Hydrate, Mycophenolate Mofetil, Mycophenolic Acid, Pimecrolimus (or its hydrate), or Sirolimus (or its hydrate). In one embodiment, an immunosuppressive medicament can be a biologically derived material, such as an immunoglobulin-containing antibody.
In still another aspect, a method for preparing a composition of the present invention comprises combining at least a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. In one embodiment, such a carrier can be a sterile saline solution or a physiologically acceptable buffer.
Physiologically acceptable buffers include, but are not limited to, a phosphate buffer or a Tris-HC1 buffer (comprising tris(hydroxymethyl)aminomethane and HC1).
For example, a Tris-HC1 buffer having pH of 7.4 comprises 3 g/1 of tris(hydroxymethyl)aminomethane and 0.76 g/1 of HC1. In yet another aspect, the buffer is 10X phosphate buffer saline ("PBS") or 5X PBS solution.
Other buffers also may be found suitable or desirable in some circumstances, such as buffers based on HEPES (N-{2-hydroxyethyllpeperazine-N'-{2-ethanesulfonic acid}) having pKa of 7.5 at 25 C and pH in the range of about 6.8-8.2; BES
(N,N-bis{2-hydroxyethy1}2-aminoethanesulfonic acid) having plc of 7.1 at 25 C and pH in the range of about 6.4-7.8; MOPS (3-{N-morpholino propanesulfonic acid) having plc of 7.2 at 25 C and pH in the range of about 6.5-7.9; l'ES (N-tris{hydroxymethyl }-methy1-2-aminoethanesulfonic acid) having pKa of 7.4 at 25 C and pH in the range of about 6.8-8.2; MOBS (4-{N-morpholino}butanesulfonic acid) having pKa of 7.6 at 25 C and pH in the range of about 6.9-8.3; DIPSO (3-(N,N-bis{2-hydroxyethyl}amino)-2-hydroxypropane) ) having pKa of 7.52 at 25 C and pH in the range of about 7-8.2;
TAPSO (2-hydroxy-3 tris(hydroxymethyl)methylamino1- I -propanesulfonic acid) ) having plc of 7.61 at 25 C and pH in the range of about 7-8.2; TAPS ({(2-hydroxy-1,1-bis(hydroxymethypethypamino}-1-propanesulfonic acid) ) having pKa of 8.4 at 25 C
and pH in the range of about 7.7-9.1; TABS (N-tris(hydroxymethyl)methy1-4-aminobutanesulfonic acid) having pKa of 8.9 at 25 C and pH in the range of about 8.2-9.6; AMPSO (N-(1,1-dimethy1-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid) ) having plc of 9.0 at 25 C and pH in the range of about 8.3-9.7; CHES
(2-cyclohexylamino)ethanesulfonic acid) having plc of 9.5 at 25 C and pH in the range of about 8.6-10.0; CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) having plc of 9.6 at 25 C and pH in the range of about 8.9-10.3; or CAPS (3-(cyclohexylamino)-1-propane sulfonic acid) having pKa of 10.4 at 25 C and pH
in the range of about 9.7-11.1.
In certain embodiments, a composition of the present invention is formulated in a buffer having a slight acidic pH, such as from about 6 to about 6.8. In such embodiments, the buffer capacity of the composition desirably allows the composition to come rapidly to a physiological pH after being administered to into the patient.

Two solutions I and II are made separately by mixing the ingredients listed in Table 1. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2-6.4 using I N NaOH to yield a composition of the present invention.

Table 1 Ingredient Amount Mixture I
Carbopol 934P NF 0.25 g Purified water 99.75 g Mixture II
Propylene glycol 5 g EDTA 0.1 mg Compound of Formula IV 50 g EXAMPLE 2:
Two mixtures I and II are made separately by mixing the ingredients listed in Table 2. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 2 Ingredient Amount Mixture I
, Carbopol 934P NF 0.25 g Purified water 99.75 g Mixture H
Propylene glycol 5 g EDTA 0.1 mg Compound of Formula IV 50 g Cyclosporine A 5 g EXAMPLE 3:
Two mixtures I and II are made separately by mixing the ingredients listed in Table 3. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture II for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 3 Ingredient Amount Mixture I
Carbopol 934P NF 0.25 g Purified water 99.75 g Mixture II
Propylene glycol 3 g Triacetin 7 g Compound of Formula H 50 g Cyclosporine A 5 g EDTA 0.1 mg EXAMPLE 4:
Two mixtures I and II are made separately by mixing the ingredients listed in Table 4. Five parts (by weight) of mixture I are mixed with twenty parts (by weight) of mixture H for 15 minutes or more. The pH of the combined mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 4 Ingredient Amount Mixture I
Carbopol 934P NF 0.25 g Purified water 99.75 g Mixture II
Propylene glycol 7 g Glycerin 3 g Compound of Formula III 50 g Cyclosporine A 5 g HAP (30%) 0.5 mg Alexidine 2HC1 1-2 ppm Note: "HAP" denotes hydroxyalkyl phosphonates, such as those known under the trade name Dequest .
EXAMPLE 5:
The ingredients listed in Table 5 are mixed together for at least 15 minutes.
The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 5 Ingredient Amount (% by weight) Povidone 1 HAP (30%) 0.05 Glycerin 3 Propylene glycol 3 Compound of Formula IV 0.5 Cyclosporine A 0.1 Tyloxapol 0.25 BAK 10-100 ppm Purified water q.s. to 100 Note: "BAK" denotes benzalkonium chloride.
EXAMPLE 6:
The ingredients listed in Table 6 are mixed together for at least 15 minutes.
The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 6 Ingredient Amount (% by weight) Povidone 1.5 HAP (30%) 0.05 Glycerin 3 Propylene glycol 3 Compound of Formula IV 0.75 Cyclosporine A 0.1 Tyloxapol 0.25 Alexidine 2HC1 1-2 ppm Purified water q.s. to 100 EXAMPLE 7:
The ingredients listed in Table 7 are mixed together for at least 15 minutes.
The pH of the mixture is adjusted to 6.2-6.4 using 1 N NaOH to yield a composition of the present invention.

Table 7 Ingredient Amount (% by weight) CMC (MV) 0.5 HAP (30%) 0.05 Glycerin 3 Propylene glycol 3 Compound of Formula IV 0.75 Cyclosporine A 0.1 Tyloxapol (a surfactant) 0.25 Alexidine 2HC1 1-2 ppm Purified water q.s. to 100 In another aspect, a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof is incorporated into an ophthalmic device that comprises a biodegradable material, and the device is implanted into a subject to provide a long-term (e.g., longer than about 1 week, or longer than about I, 2, 3, 4, 5, or 6 months) treatment of the chronic inflammatory condition. Such a device may be implanted by a skilled physician in the subject's ocular or periocular tissue.
In still another aspect, a method for treating, reducing, or alleviating dry eye condition or an ophthalmic disorder, which has an etiology in inflammation, comprises:
(a) providing a composition comprising a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) administering to a subject an amount of the composition at a frequency sufficient to treat, reduce, or alleviate the dry eye condition or the ophthalmic disorder in the subject.
In one embodiment, the DIGRA is selected from among those disclosed above.

In another embodiment, the composition further comprises an immunosuppressive agent selected from among those disclosed above. The concentration of the DIGRA, a prodrug thereof, a pharmaceutically acceptable salt thereof, or the immunosuppressive agent is slecetd from among the ranges disclosed above.
In another aspect, a composition of the present invention is administered topically under an eyelid or on the ocular surface of the subject. In still another aspect, a composition of the present invention is injected into the conjunctival tissue of the subject.
In yet another aspect, a composition of the present invention is administered topically once daily, more than once per day, once every other day, or once a week.
COMPARISON OF GLUCOCORTICOIDS AND DIGRAS
One of the most frequent undesirable actions of a glucocorticoid therapy is steroid diabetes. The reason for this is the stimulation of gluconeogenesis in the liver by the induction of the transcription of hepatic enzymes involved in gluconeogenesis and metabolism of free amino acids that are produced from the degradation of proteins (catabolic action of glucocorticoids). A key enzyme of the catabolic metabolism in the liver is the tyrosine aminotransferase ("TAT"). The activity of this enzyme can be determined photometrically from cell cultures of treated rat hepatoma cells.
Thus, the gluconeogenesis by a glucocorticoid can be compared to that of a DIGRA by measuring the activity of this enzyme. For example, in one procedure, the cells are treated for 24 hours with the test substance (a DIGRA or glucocorticoid), and then the TAT
activity is measured. The TAT activities for the selected DIGRA and glucocorticoid are then compared. Other hepatic enzymes can be used in place of TAT, such as phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, or fructose-2,6-biphosphatase. Alternatively, the levels of blood glucose in an animal model may be measured directly and compared for individual subjects that are treated with a glucocorticoid for a selected condition and those that are treated with a DIGRA for the same condition.

Another undesirable result of glucocorticoid therapy is increased IOP in the subject. IOP of subjects treated with glucoicorticoid and DIGRA for a condition may be measured directly and compared.
TESTING: Comparison of the DIGRA Having Formula IV With Two Corticosteroids and One NSAID in Treating Inflammation 1. IN I'RODUCTION
Inflammatory processes are multidimensional in origin, and are characterized by complex cellular and molecular events involving numerous components all of which have not been identified. Prostaglandins are among these mediators and play an important role in certain forms of ocular inflammation. Paracentesis of the anterior chamber in the rabbit eye induces inflammatory reaction due to the disruption of the blood-aqueous barrier ("BAB"), which is mediated, at least in part, by prostaglandin E2 [References 1 ¨3 below]. Intraocular or topical administration of PGE2 disrupts the BAB. [Reference 4, below] The treatment schedule adopted in this study was similar to the clinical NSAIDs (Ocufen) treatment schedule used by surgeons for patients before cataract surgery. We investigated a dissociated glucocorticoid receptor agonist ("BOL-303242-X", compound having Formula IV above) at different doses on rabbit paracentesis model evaluating aqueous biomarkers levels, and iris-ciliary body MPO
activity in comparison with vehicle, dexamethasone, loteprednol and flurbiprofen.
2. METHODS
2.1 Drugs and Materials 2.1.1. Test articles BOL-303242-X (0.1%, 0.5% and 1% topical formulations), lot 2676-MLC-107, Bauch & Lomb Incorporated ("B&L") Rochester, USA.
Vehicle (10% PEG 3350; 1% Tween 80; phosphate buffer pH 7.00), lot 2676-MLC-107, B&L Rochester, USA.

Visumetazone (0.1% Dexamethasone topical formulation), lot T253, Visufarma, Rome, Italy.
Lotemax (0.5% Loteprednol topical formulation), lot 078061, B&L TOM, Macherio, Italy.
Ocufen (0.03% Flurbiprofen topical formulation), lot E45324, Allergan, Westport, Ireland.
2.2 Animals Species: Rabbit Breed: New Zealand Source: Morini (Reggio Emila, Italy) Sex: Male Age at Experimental Start: 10 weeks.
Weight Range at Experimental Start: 2.0-2.4 Kg Total Number of Animals: 28 Identification: Ear tagged with an alphanumeric code (i.e. Al means test article A
and animal 1).
Justification: The rabbit is a standard non-rodent species used in pharmacodynamic studies. The number of animals used in this study is, in judgment of the investigators involved, the minimum number necessary to properly perform this type of study and it is consistent with world wide regulatory guidelines.

Acclimation/Quarantine: Following arrival, a member of the veterinary staff assessed animals as to their general health. Seven days elapsed between animal receipt and the start of experiment in order to acclimate animals to the laboratory environment and to observe them for the development of infection disease.
Animal Husbandry: All the animals were housed in a cjeaned and disinfected room, with a constant temperature (22 1 C), humidity (relative, 30%) and under a constant light-dark cycle (light on between 8.00 and 20.00). Commercial food and tap water were available ad libitum. Their body weights were measured just before the experiment (Table T-1). All the animals had a body weight inside the central part of the body weight distribution curve (10%). Four rabbits were replaced with animals of similar age and weight from the same vendor because three of them showed signs of ocular inflammation and one was dead upon arrival.
Animals Welfare Provisions: All experiments were carried out according to the ARVO (Association for Research in Vision and Ophthalmology) guidelines on the use of animals in research. No alternative test system exists which have been adequately validated to permit replacement of the use of live animals in this study.
Every effort has been made to obtain the maximum amount of information while reducing to a minimum the number of animals required for this study. To the best of our knowledge, this study is not unnecessary or duplicative. The study protocol was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Catania and complies with the acceptable standards of animal welfare care.
2.3 Experimental Preparations 2.3.1 Study design and randomization Twenty-eight rabbits were randomly allocated into 7 groups (4 animals/each) as shown in the table below.
Table 8 Group No of Treatment Observations and Termination and rabbits measurements assays 4 CTR 50 pl drops at Clinical observations Termination 180, 120, 90, and pupillary immediately after II 4 I% BOL and 30 min diameter at 180 and 5 the second prior to first min before the first paracentesis.
iii4 0.5% BOL paracentesis, paracentesis, and at 5 and at 15, 30, min before the IV 4 0.1 BOL 90 min after second paracentesis. Aqueous humor %
the first collected for PGE,, paracentesis. protein, leukocytes V 4 0.5% LE Paracentesis at 0 and and LTB4 2 hours. measurements.
VI 4 0.1% Dex VII 4 0.03% F Iris-ciliary body collected for MPO
activity measurement.
CTR=vehicle; BOL=BOL-303242-X; LE=loteprednol etabonate; Dex=dexamethasone;
F=flurbiprofen To each test article was randomly assigned a letter from A to G
A = vehicle (10% PEG3350/1% Tween 80/PB pH 7.00) B = Ocufen (Fluorbiprofen 0.03%) C = Visumetazone (Desmethasone 0.1%) D = Lotemax (Loetprednol etabonate 0.5%) E = BOL-303242-X 0.1% (1 mg/g) F = BOL-303242-X 0.5% (5 mg/g) G = BOL-303242-X I% (10 mg/g) 2.3.2 Reagent preparation for MPO assay 2.3.2.1 Phosphate buffer (50mM; pH=6) 3.9g of NaH2PO4 2H20 were dissolved in a volumetric flask to 500m1 with water.

The pH was adjusted to pH=6 with 3N NaOH.
2.3.2.2 Hexa-decyl-trimethyl-ammonium bromide (0.5%) 0.5g of hexa-decyl-trimethyl-ammonium bromide was dissolved in I 00m1 phosphate buffer.
2.3.2.3 o-dianisidine 2HCI (0.0167%) / H202 (0.0005%) solution The solution was prepared freshly. Ten microliters of H202 (30 wt.%) were diluted to lml with water (solution A). 7.5mg o-dianisidine 2HC1 were dissolved in 45m1 of phosphate buffer and 75 1 of solution A were added.
2.4 Experimental Protocols 2.4.1 Animals treatment and sample collection Each rabbit was placed in a restraint device and tagged with the alphanumeric code. The formulations were instilled (50 I) into the conjunctival sac of both eyes 180, 120, 90 and 30 min before the first paracentesis; then 15, 30, 90 min after the first paracentesis. To perform the first paracentesis the animals were anaesthetized by intraveneous injection of 5mg/kg Zoletil (Virbac; 2.5mg/kg tiletamine HC1 and 2.5mg/kg zolazepam HC1) and one drop of local anesthetic (Novesina , Novartis) was administered to the eye. Anterior chamber paracentesis was performed with a 26 G
needle attached to a tuberculin syringe; the needle was introduced into the anterior chamber through the cornea, taking care not to damage the tissues. Two hours after the first paracentesis, the animals were sacrificed with 0.4 ml Tanax (Intervet International B.V.) and the second paracentesis was performed. About 100 pl of aqueous humor were removed at the second paracentesis. Aqueous humor was immediately split in four aliquots and stored at ¨80 C until analysis. Then both eyes were enucleated and the iris-ciliary body was carefully excised, placed in polypropylene tubes, and stored at ¨80 C
until analysis.
2.4.2 Pupillary diameter measurement The pupillary diameter of both eyes was measured with a Castroviejo caliper min and 5 min before the first paracentesis and 5 min before the second paracentesis.

2.4.3 Clinical evaluation The clinical evaluation of both eyes was performed by a slit lamp (4179-T;
Sbisa, Italy) at 180 min and 5 min before the first paracentesis and 5 min before the second paracentesis. The clinical score was assigned according to the following scheme:
0 = normal 1 = discrete dilatation of iris and conjunctival vessels 2 = moderate dilatation of iris and conjunctival vessels 3 = intense iridal hyperemia with flare in the anterior chamber 4 = intense iridal hyperemia with flare in the anterior chamber and presence of fibrinous exudates.
2.4.4 Prostaglandin E2 (PGE2) measurement For the quantitative determination of PGE2 in the aqueous humor we used the PGE2 Immunoassay kit (R&D Systems; Cat.No. KGE004; Lot.No. 240010). Eleven microliters or 16111 of aqueous humor were diluted to 110111 or 160 1 with the calibrator diluent solution provided with the kit. One hundred microliters of samples and of standards were load into a 96-well plate and recorded in a plate layout.
Samples were treated following the assay procedure described in the kit. A microplate reader (GDV, Italy; model DV 990 BN6) set at 450 nm (wavelength correction at 540 nm) was used for making the calibration and analyzing the samples.
2.4.5 Protein measurement For protein concentration determination in the aqueous humor we used the Protein Quantification Kit (Fluka; Cat.No. 77371; Lot.No. 1303129). Five microliters of aqueous humor were diluted to 100[11 with water. Twenty microliters of samples and of standards were load into a 96-well plate and recorded in a plate layout.
Samples were treated following the assay procedure described in the kit. A microplate reader (GDV, Italy; model DV 990 BN6) set at 670 nm was used for making the calibration and analyzing the samples.

2.4.6 Leukocytes (PMN) measurement For the determination of the number of leukocytes we used a haemocytometer (Improved Neubauer Chamber; Brigth-line, Hausser Scientific) and a Polyvar 2 microscope (Reichert-Jung).
2.4.7 Leucotriene B4 (LTB4) measurement For the quantitative determination of LTB4 concentration in the aqueous humor we used the LTB4 Immunoassay kit (R&D Systems; Cat.No. KGE006; Lot.No.
243623).
I 1 1 of aqueous humor were diluted to 110111 with the calibrator diluent solution provided with the kit. 100 Ill of samples and of standards were load into a 96-well plate and recorded in a plate layout. Samples were treated following the assay procedure described in the kit. A microplate reader (GDV, Italy; model DV 990 BN6) set at 450 nm (wavelength correction at 540 nm) was used for making the calibration and analyzing the samples.
2.4.8 Myeloperoxidase (MPO) measurement The activity of MPO was measured as previously described by Williams et a1.[5]

The iris-ciliary bodies were carefully dried, weighed and immersed in lml of hexa-decyl-trimethyl-ammonium bromide solution. Then, the samples were sonicated for 10 sec on ice by a ultrasound homogenizer (HD 2070, Bandelin electronic), freeze-thawed three times, sonicated for 10 sec and centrifuged at 14,000 g for 10 min to remove cellular debris. An aliquot of the supernatant (40-200 I) was diluted to 3m1 with the o-dianisidine 2HC1/ H202 solution. The change in absorbance at 460nm was continuously monitored for 5 min by a spectrophotometer (UVNis Spectrometer Lambda EZ 201;
Perkin Elmer). The slope of the line (A/min) was determined for each sample and used to calculate the number of units of MPO in the tissue as follows:
MPOunit I g = min) .106 E=111- mg were = 11.3 mM-I.

Values were expressed as units of MPO/g of tissue.
2.5 Data Analysis Pupillary diameter, PGE2, protein, PMN, and MPO were expressed as mean SEM. Statistical analysis was performed using one way ANOVA followed by a Newman-Keuls post hoc test. Clinical score was expressed as % of eyes and the statistical analysis was performed using Kruskal-Wallis followed by a Dunn post hoc test. P<0.05 was considered statistically significant in both cases. Prism 4 software (GraphPad Software, Inc.) was used for the analysis and graphs.
3. RESULTS
3.1 Pupillary diameter measurement The raw data are displayed in Tables T-2 and T-3. No statistical significance was found between the CRT and all the treatments.
3.2 Clinical evaluation The raw data are displayed in Tables T-4 and T-5. Only the 0.5% LE group showed a significant difference vesus CTR (p<0.05).
3.3 Prostaglandin E2 (PGE2) measurement The raw data are displayed in Tables T-6 and T-7. The treatments 0.03% F, 0.5%

LE, 0.1% BOL, and 0.5% BOL were statistically significant versus CTR (p<0.05).
3.4 Protein measurement The raw data are displayed in Tables T-8 and T-9. It has been found a statistical significance for the treatments 0.03% F and 1% BOL vs CTR with p<0.001, and 0.5%
BOL vs CTR with p<0.05.

3.5 Leukocytes (PMN) measurement The raw data are displayed in Tables T-10 and T-I 1. All the treatments were statistically significant vs CTR (p<0.001).
, 3.6 Leucotriene B4 (LTB4) measurement All samples were under the limit of quantification (about 0.2 ng/ml) of the assay.
3.7 Myeloperoxidase (MPO) measurement The raw data are displayed in Tables T-12 and 1-13. It has been found a statistical significance for the all the treatments vs CTR with p<0.01 for 0.03% F, and p<0.001 for 0.1% Dex, 0.5% LE, 0.1% BOL, 0.5% BOL and 1% BOL.
4. DISCUSSION
The preliminary conclusions from the data generated are:
= BOL-303242-X is active in this model.
= There was not a large difference between these concentrations of BOL-and NSAID and steroid positive controls.
There was not a profound dose-response for BOL-303242-X, perhaps because we are at either maximal efficacy or maximal drug exposure at these doses.
However, the results show that BOL-303242-X is as effective an anti-inflammatory drug as some of the commonly accepted prior-art steroids or NSAID. Some other very preliminary data (not shown) suggest that BOL-303242-X does not have some of the side effects of corticosteroids.

5. REFERENCES
1. Eakins KE (1977). Prostaglandin and non prostaglandin-mediated breakdown of the blood-aqueous barrier. Exp Eye Res, 25, 483-498.
2. Neufeld AH, Sears ML (1973). The site of action of prostaglandin E2 on the disruption of the blood-aqueous barrier in the rabbit eye. Exp Eye Res, 17, 445-448.
3. Unger WG, Cole DP, Hammond B (1975). Disruption of the blood-aqueous barrier following paracentesis in the rabbit. Exp Eye Res, 20, 255-270.
4. Stjernschantz J (1984). Autacoids and Neuropeptides. In: Sears, ML (ed) Pharmacology of the Eye. Springer-Verlag, New York, pp 311-365.
5. Williams RN, Paterson CA, Eakins KE, Bhattacherjee P (1983) Quantification of ocular inflammation: evaluation of polymorphonuclear leukocyte infiltration by measuring myeloperoxidase activity. Curr Eye Res 2:465-469.
Table T-1: Rabbit body weight measured just before the experiment Rabbit ID Sex Body weight (g) Al M 2090 Cl M 2160 El M 2170 , Fl M 2190 Mean S.D. 2236.8 89.2 Table T-2 Raw data of pupillary diameter at -180 min (basal), -5 min (5 min before the first paracentesis) and at +115 min (5 min before the second paracentesis), and calculated difference between the value at +115 min and the value at -180 min.
Treatment Rabbit ID Eye Diameter (mm) TI: -180 min T2: -5 min T3: +115 min A(T3 - T1) CTR Al DX 6.0 5.5 4.0 -2.0 SX 5.5 5.5 4.0 -1.5 A2 DX 6.0 6.5 4.5 -1.5 SX 6.0 6.5 5.0 -1.0 A3 DX 6.5 6.5 5.0 -1.5 SX 6.5 6.5 5.0 -1.5 A4 DX 6.0 6.5 5.0 -1.0 SX 6.0 6.5 5.0 -1.0 0.03% F Bl DX 5.0 6.0 4.0 -1.0 _ SX 5.0 6.0 3.5 -1.5 B2 DX 7.0 6.5 5.5 -1.5 SX 6.0 7.0 5.0 -1.0 B3 DX 6.0 6.5 4.5 -1.5 SX 6.0 6.5 6.0 0.0 B4 DX 5.5 6.0 5.5 0.0 SX 6.0 5.5 5.0 -1.0 , 0.1% Dex Cl DX 6.0 5.5 5.5 -0.5 SX 7.0 6.5 5.5 -1.5 C2 DX 5.5 6.5 6.0 0.5 SX 5.5 6.0 5.5 0.0 C3 DX 6.5 6.0 4.5 -2.0 SX 6.5 6.5 5.0 -1.5 C4 DX 6.5 7.0 6.0 -0.5 SX 7.0 7.5 6.5 -0.5 0.5% LE DI DX 6.0 6.0 4.5 -1.5 SX 6.0 6.0 5.0 -1.0 D2 DX 6.5 6.5 5.5 -1.0 SX 6.5 6.5 5.5 -1.0 D3 DX 6.0 6.0 6.0 0.0 SX 6.5 6.5 6.0 -0.5 D4 DX 6.5 6.5 6.0 -0.5 SX 6.5 6.5 5.0 -1.5 0.1% BOL El DX 6.5 6.5 5.0 -1.5 SX 6.5 6.5 6.0 -0.5 E2 DX 6.5 7.0 5.0 -1.5 SX 6.5 7.0 6.0 -0.5 E3 DX 7.0 7.0 6.0 -1.0 SX 7.5 7.5 6.5 -1.0 E4 DX 7.0 6.5 5.5 -1.5 SX 7.0 7.0 5.5 -1.5 0.5% BOL Fl DX 8.0 8.0 6.5 -1.5 SX 8.0 8.0 6.5 -1.5 F2 DX 7.0 7.0 6.5 -0.5 SX 7.0 7.0 6.0 -1.0 F3 DX 7.5 7.5 7.0 -0.5 SX 8.0 8.0 7.0 -1.0 F4 DX 7.0 7.0 6.0 -1.0 SX 7.5 7.0 6.5 -1.0 1% BOL GI DX 6.0 6.0 5.5 -0.5 SX 6.5 6.5 5.0 -1.5 G2 DX 6.0 6.5 5.0 -1.0 SX 6.0 6.5 5.0 -1.0 G3 DX 6.5 7.0 5.5 -1.0 SX 6.5 7.0 5.0 -1.5 G4 DX 6.5 6.5 6.0 -0.5 SX 6.5 6.0 6.0 -0.5 Table T-3 Difference between the value of pupillary diameter at T3=+115 min (5 min before the second paracentesis) and the value at T1=-180 min (basal) (Mean SEM).
Treatment Rabbit Group ID Mean (mm) SEM n A(T3 - TI) CTR A -1.4 0.12 8 0.03% F B -0.9 0.22 , 8 0.1% Dex C -0.8 0.30 8 0.5% LE D -0.9 0.18 8 0.1% BOL E -1.1 0.16 8 0.5% BOL F -1.0 0.13 8 1% BOL G -0.9 0.15 8 Table 1-4 Raw data of clinical score at ¨180 min (basal), -5 min (5 min before the first paracentesis) and at +115 min (5 min before the second paracentesis).
Treatment Rabbit ID Eye Clinical Score -180 min -5 min +115 min CTR Al DX 0 1 3 0.03%F B1 DX 0 0 2 0.1% Dex Cl DX 0 0 1 Ctl DX 0 0 1 0.5% LE DI DX 0 0 2 0.1% BOL El DX 0 0 2 0.5% BOL Fl DX 0 0 2 I% BOL GI DX 0 0 2 Table T-5 Clinical score expressed as percentage of eyes at ¨180 min (basal), -5 min (5 min before the first paracentesis) and at +115 min (5 min before the second paracentesis).
Treatment Rabbit Group N Score (%) ID (eyes) 0 I 2 3 4 -180 min 0.03%F B 8 100 -- -- -- --0.1% Dex C 8 100 -- -- -- --0.5% LE D 8 100 -- -- -- --0.1% BOL E . 8 100 -- -- -- --0.5% BOL F 8 100 -- -- -- --1% BOL G 8 100 -- -- -- ---5 min 0.03%F B 8 100 -- -- -- --0.1% Dex C 8 75 25 -- -- --0.5% LE D 8 100 -- -- -- --0.1% BOL E 8 100 -- -- -- --0.5% BOL F 8 100 -- -- -- --1% BOL G 8 100 -- -- -- --+115 min 0.03%F B 8 -- -- 100 -- --0.1% Dex C 8 -- 75 -- 25 --0.5% LE D 8 -- 75 25 --0.1% BOL E 8 -- -- 75 25 --0.5% BOL F 8 -- 37.5 62.5 -- --1% BOL G 8 -- -- 100 -- --Table T-6 Raw data of PGE2 levels in aqueous humor samples collected at the second paracentesis Treatment Sample PGE, (ng/ml) CTR 2-A 1 -DX 3.81 2-A 1 -SX 2.91 2-A2-DX 4.77 2-A3-DX 1.46 2-A3-SX 3.00 2-A4-DX 1.87 2-A4-SX 1.88 0.03% F 2-B I -DX 1.04 2-B1-SX 0.75 2-B2-DX 0.85 2-B2-SX 1.11 2-B3-DX 2.11 2-B3-SX 0.93 2-B4-DX 0.61 2-B4-SX 2.11 0.1% Dex 2-C1-DX 2.51 2-C2-DX 2.32 2-C3-DX 2.10 2-C3-SX 3.03 2-C4-DX 2.32 2-C4-SX 1.30 0.5% LE 2-D1-DX 2N/D

2-D2-SX 0.23 2-D3-SX 0.68 2-D4-SX 1.10 0.1% BOL 2-El-DX 1.62 2-E1-SX 1.88 2-E2-DX 2.15 2-E2-SX 0.70 2-E3-DX 1.34 2-E3-SX 1.03 0.5% BOL 2-Fl -DX 2.31 2-F I -SX 2.59 2-F2-SX 0.53 2-F3-DX 0.75 2-F3-SX 0.80 2-F4-DX 1.62 2-F4-SX 1.09 1% BOL 2-G1-DX 0.50 2-G1-SX 1.87 2-G2-DX 1.71 2-G2-SX 4.04 2-G3-DX 1.11 2-G3-SX 3.78 'N/A = not available 2N/D = not detectable, under the limit of quantification Table T-7 Levels of PGE2 in aqueous humor samples collected at the second paracentesis (Mean SEM).
Treatment Sample Group Mean SEM
(ng/ml) CTR A 2.815 0.449 7 0.03% F B 1.189 0.209 8 0.1% Dex C 2.263 0.232 6 0.5% LE D 0.672 0.250 3 0.1% BOL E 1.452 0.221 6 0.5% BOL F 1.384 0.306 7 1% BOL G 2.168 0.586 6 Table T-8 Raw data of protein levels in aqueous humor samples collected at the second paracentesis Treatment Sample Protein (mg/ml) CTR 2-A 1 -DX 50.24 2-Al-SX 53.51 2-A2-DX 28.73 2-A3-DX 40.09 2-A3-SX 30.84 2-A4-DX 41.79 2-A4-SX 30.35 0.03% F 2-B1-DX 20.78 2-B1-SX 28.80 2-B2-SX 23.41 2-B3-DX 20.21 2-B3-SX 17.53 2-B4-DX 15.12 2-B4-SX 20.52 0.1% Dex 2-C1-DX 31.31 2-C2-DX 31.81 2-C3-DX 35.95 2-C3-SX 37.15 2-C4-DX 32.12 2-C4-SX 32.40 0.5% LE 2-D1-DX 36.14 2-D I -SX 39.10 2-D2-DX 34.69 2-D2-SX 26.10 2-D3-DX 26.30 2-D3-SX 28.16 2-D4-DX 40.90 2-D4-SX 39.85 0.1% BOL 2-E1-DX 34.87 2-E1-SX 34.41 2-E2-DX 31.14 2-E2-SX 22.82 2-E3-DX 29.46 2-E3-SX 31.69 2-E4-DX 35.70 2-E4-SX 49.25 0.5% BOL 2-Fl -DX 33.98 2-Fl-SX 33.65 2-F2-DX 19.99 2-F2-SX 27.11 2-F3-DX 19.72 2-F3-SX 36.35 2-F4-DX 27.71 2-F4-SX 32.24 1% BOL 2-G1-DX 20.99 2-G1-SX 21.48 2-G2-DX 15.11 2-G2-SX 20.28 2-G3-DX 20.94 2-G3-SX 21.89 2-G4-DX 20.03 2-G4-SX 30.76 'N/A = not available Table T-9 Protein levels in aqueous humor samples collected at the second paracentesis (Mean SEM).
Treatment Sample Group Mean SEM
(mg/ml) CTR A 39.364 3.754 7 0.03% F B 20.910 1.648 7 0.1% Dex C 33.457 1.001 6 0.5% LE D 33.905 2.190 8 0.1% BOL E 33.667 2.655 8 0.5% BOL F 28.844 2.249 8 1% BOL G 21.435 1.529 8 Table T-10 Raw data of PMN numbers in aqueous humor samples collected at the second paracentesis Treatment Sample PMN
(number/ill) CTR 2-Al -DX 90 2-A2-DX = 70 0.03% F 2-B1-DX 50 0.1% Dex 2-C1-DX 20 0.5% LE 2-D1-DX N/A

0.1% BOL 2-El-DX N/A
2-El-SX 20 0.5% BOL 2-F1-DX 40 1% BOL 2-G1-DX 30 1N/A = not available Table T-11 PMN numbers in aqueous humor samples collected at the second paracentesis (Mean SEM).
Treatment Sample Group Mean SEM
(number/ 1) C IR A 68.571 6.701 7 0.03% F B 30.000 5.345 7 0.1% Dex C 30.000 5.164 6 0.5% LE D 28.333 4.014 6 0.1% BOL E 28.333 5.426 6 0.5% BOL 21.250 4.407 8 1% BOL G 28.750 2.950 8 Table T-12 Raw data of MPO activity in iris-ciliary body samples collected after the second paracentesis.
Treatment Sample Iris-ciliary body rVolume 2 A/min MPO Unit/g weight (mg) (jil) CTR Al-DX 41.7 40 0.021 1.11 Al-SX 42.3 40 0.024 1.26 A2-DX 46.6 40 0.039 1.85 A2-SX 40.5 40 0.037 2.02 A3-DX 48.9 40 0.075 3.39 A3-SX 51.1 40 0.049 2.12 A4-DX 36.6 40 0.013 0.79 A4-SX 38.8 40 0.019 1.08 0.03%F BI-DX 39.5 100 0.049 1.10 B I -SX 42.7 100 0.082 1.70 B2-DX 34.1 100 0.013 0.34 B2-SX 36.6 100 0.031 0.75 B3-DX 45.6 100 0.038 0.74 B3-SX 38.0 100 0.027 0.63 B4-DX 40.1 100 0.033 0.73 B4-SX 42.6 100 0.061 1.27 0.1% Dex C1-DX 36.4 100 0.029 0.71 CI -SX 45.8 100 0.031 0.60 C2-DX 42.9 100 0.064 1.32 C2-SX 42.7 100 0.023 0.48 C3-DX 43.0 100 0.019 0.39 C3-SX 46.8 100 0.024 0.45 C4-DX 42.3 100 0.023 0.48 C4-SX 36.1 100 0.021 0.51 0.5% TY D I -DX 38.9 200 0.026 0.30 D I -SX 44.7 200 0.053 0.51 D2-DX 35.9 200 0.067 0.81 D2-SX 40.7 /00 0.055 0.60 D3-DX 46.3 200 0.076 0.73 D3-SX 41.9 200 0.096 1.01 D4-DX 46.7 3N/A N/A N/A
D4-SX 32.9 N/A N/A N/A

0.1% BOL El-DX 43.6 100 0.051 1.04 E 1 -SX 37.2 100 0.042 1.00 E2-DX 32.6 100 0.042 1.14 E2-SX 37.4 100 0.045 1.06 E3-DX 36.2 100 0.050 1.22 E3-SX 45.1 100 0.031 0.61 E4-DX 30.4 100 0.036 1.05 E4-SX 42.3 100 0.031 0.65 0.5% BOL F I -DX 45.8 100 0.044 0.85 F1-SX 38.2 100 0.040 0.93 F2-DX 34.9 100 0.031 0.79 F2-SX 42.0 100 0.049 1.03 F3-DX 39.1 100 0.033 0.75 F3-SX 40.6 100 0.034 0.74 F4-DX 36.2 100 0.022 0.54 F4-SX 39.5 100 0.026 0.58 1% BOL G1 -DX 32.4 100 0.024 0.66 G I -SX 43.1 100 0.033 0.68 G2-DX 30.6 100 0.017 0.49 G2-SX 39.9 100 0.018 0.40 G3-DX 41.3 100 0.016 0.34 G3-SX 44.9 100 0.052 1.02 G4-DX 36.6 100 0.013 0.31 G4-SX 36.9 100 0.018 0.43 'Volume = aliquot ( 1) of the supernatant diluted to 3m1 for the analysis.
2A/min = mean of the slope of the line recorded every 15 sec for 5 min 3N/A = not available Table T-13 MPO activity in iris-ciliary body samples collected after the second paracentesis (Mean SEM).
Treatment Sample Group Mean SEM n MPO Unit/g CTR A 1.703 0.297 8 0.03% F B 0.906 0.151 8 0.1% Dex C 0.618 0.106 8 0.5% LE D 0.661 0.102 6 0.1% BOL E 0.971 0.079 8 0.5% BOL F 0.775 0.058 8 1% BOL G 0.542 0.083 8 , The scope of the claims should not be limited to the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

1. A composition for treating, reducing, or alleviating dry eye condition that requires rewetting of the eye, the composition comprising a dissociated glucocorticoid receptor agonist ("DIGRA") or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier wherein the DIGRA comprises a compound having Formula IV
and wherein the composition causes a lower level of at least an adverse side effect of glaucoma or cataract in a subject than at least a glucocorticoid used to treat, reduce, or alleviate said dry eye condition.

2. The composition of claim 1, wherein said at least a glucocorticoid is selected from the group consisting of dexamethasone, prednisone, prednisolone, methylprednisolone, medrysone, triamcinolone, loteprednol etabonate, physiologically acceptable salts thereof, combinations thereof, and mixtures thereof.

3. The composition of claim 1, wherein the level of said at least an adverse side effect is determined at about 30 days after the composition is first administered to, and is present in, the subject.

4. Use of a composition comprising a DIGRA or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier in an amount of the composition and at a frequency sufficient to treat, reduce, or alleviate the dry eye condition, wherein the DIGRA
has Formula IV

and wherein the composition causes a lower level of at least an adverse side effect of glaucoma or cataract in a subject than at least a glucocorticoid used to treat, reduce, or alleviate said dry eye condition.

5. The use of claim 4, wherein the composition comprises the composition of claim 2.

6. A method for manufacturing a composition for treating a dry eye condition, the method comprising:
(a) providing a DIGRA having Formula IV
or a pharmaceutically acceptable salt thereof; and (b) combining said DIGRA or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.